Fluoromethyl-substituted pyrrole carboxamides as cav2.2 calcium channel blockers

ABSTRACT

The invention relates to pyrrole carboxamides bearing a fluoromethyl-moiety as voltage gated calcium channel blockers, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.

PRIORITY

This application is a continuation of International Patent ApplicationNo. PCT/EP2014/003430, filed Dec. 18, 2014, which claims priority ofEuropean Patent Application 13005933.0, filed Dec. 19, 2013, thedisclosures of which patent applications are incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates to substituted pyrrole-2-yl-carboxamides bearing afluorinated methyl moiety in 5-position as voltage gated Ca-channel(CaV) blockers, to pharmaceutical compositions containing thesecompounds and also to these compounds for use in the treatment and/orprophylaxis of pain and further diseases and/or disorders.

BACKGROUND OF THE INVENTION

Ion channels are proteins that form pores in membranes of biologicalcells and control the flow of ions down their electrochemical gradient.They are involved in the regulation of a wide range of cellularfunctions in both excitable and nonexcitable cells and provideattractive therapeutic targets for the treatment of various diseases.

In the somatosensory context, CaV2.2 channels, specific cellular plasmamembrane calcium channels that belong to a diverse superfamily ofvoltage-gated calcium channels (VGCCs), were demonstrated to play animportant role in spinal nociceptive processing.

The critical role of CaV2.2 in pain processing was underlined by theclinical efficacy of the intrathecally delivered, selective CaV2.2channel antagonist Ziconotide (SNX-111; Prialt™), a synthetic peptidederived from a ω-(omega)-conotoxin peptide (Miljanich, 2004, Curr. Med.Chem., 11(23), p. 3029-40; Staats et al., 2004, JAMA, 291(1), p. 63-70).Inthrathecal administration of Ziconotide is required in order to reachthe ion channel in presynaptic terminals of sensory neurons in thespinal cord. Common side effects of Ziconotide include memoryimpairment, dizziness, nystagmus, speech disorder, nervousness,somnolence and abnormal gait (Rauck et al., 2009, Pain Pract., 9, p.327-37), which have been attributed to the inhibition of CaV2.2 channelsin the brain by Ziconotide.

Therefore, a demand remains for the development of orally availableCaV2.2 calcium channel blockers that show the desired qualities andeffectively block CaV2.2 calcium channels in the nociceptive signalingpathway.

1,4-disubstituted pyrrol-2-yl carboxylic acid amides are known fromWO2007/141039 A1.

SUMMARY OF THE INVENTION

The present invention describes small molecule CaV2.2 channel blockers.

It was therefore an object of the invention to provide novel compounds,preferably having advantages over the prior-art compounds. The compoundsshould be suitable in particular as pharmacological active ingredientsin pharmaceutical compositions, preferably in pharmaceuticalcompositions for the treatment and/or prophylaxis of disorders ordiseases which are at least partially mediated by CaV2.2 calciumchannels.

This object is achieved by the subject matter described herein.

It has surprisingly been found that the compounds of general formula(I), as given below, display outstanding affinity to CaV2.2 calciumchannels and are therefore particularly suitable for the prophylaxisand/or treatment of disorders or diseases which are at least partiallymediated by CaV2.2 calcium channels.

The present invention therefore relates to a compound of general formula(I),

n represents 0, 1 or 2;m represents 0 or 1 with the proviso that n≧m;X is selected from the group consisting of O, S, NH and N—C₁₋₆-alkyl;R¹, R² and R³, are each independently of one another selected from thegroup consisting of H; F; Cl; Br; I; NO₂; CN; C₁₋₆-alkyl; CF₃; CF₂H;CFH₂; CF₂Cl; CFCl₂; C(═O)—H; C(═O)—C₁₋₆-alkyl; C(═O)—OH;C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH); C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl);C(═O)—N(C₁₋₆-alkyl)₂; C(═N—OH)—H; C(═N—OH)—C₁₋₆-alkyl;C(═N—O—C₁₋₆-alkyl)-H; C(═N—O—C₁₋₆-alkyl)-C₁₋₆-alkyl; OH; OCF₃; OCF₂H;OCFH₂; OCF₂Cl; OCFCl₂; O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl;O—C(═O)—O—C₁₋₆-alkyl; O—(C═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(C₁₋₆-alkyl)₂;O—S(═O)₂—C₁₋₆-alkyl; O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₆-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)(C₁₋₆-alkyl); O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)(C₁₋₆-alkyl);N(H)—C(═O)—N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—NH₂;N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂OH;N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl); N(H)—S(═O)₂N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—OH; N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—NH₂;N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₆-cycloalkyl; 3 to 7 membered heterocyclyl;O—C₃₋₆-cycloalkyl or O-(3 to 7 membered heterocyclyl);R⁴ represents CH₂F; CHF₂, or CF₃;R⁵ represents H, C₁₋₆-alkyl, branched or unbranched, unsubstituted ormono- or poly-substituted, a C₃₋₆-cycloalkyl or a 3 to 7 memberedheterocyclyl, in each case unsubstituted or mono- or polysubstituted;OH; O—C₁₋₆-alkyl; NH₂; N(H)—C₁₋₆-alkyl; N(—C₁₋₆-alkyl)₂ orSO₂(—C₁₋₆-alkyl);Het represents 5-, 6-, 8-, 9- or 10-membered heteroaryl, eachsubstituted by zero or one or two or three substituents of the groupconsisting of R⁶, R⁷ and R⁸,wherein R⁶, R⁷ and R⁸, are each independently of one another selectedfrom the group consisting of F; Cl; Br; I; NO₂; CN; C₁₋₆-alkyl; CF₃;CF₂H; CFH₂; CF₂Cl; CFCl₂; C(═O)—H; C(═O)—C₁₋₆-alkyl; C(═O)—OH;C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH); C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl);C(═O)—N(C₁₋₆-alkyl)₂; C(═N—OH)—H; C(═N—OH)—C₁₋₆-alkyl;C(═N—O—C₁₋₆-alkyl)-H; C(═N—O—C₁₋₆-alkyl)-C₁₋₆-alkyl; OH; OCF₃; OCF₂H;OCFH₂; OCF₂Cl; OCFCl₂; O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl;O—C(═O)—O—C₁₋₆-alkyl; O—(C═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(C₁₋₆-alkyl)₂;O—S(═O)₂—C₁₋₆-alkyl; O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₆-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)(C₁₋₆-alkyl); O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)(C₁₋₆-alkyl);N(H)—C(═O)—N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—NH₂;N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂OH;N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl); N(H)—S(═O)₂N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—OH; N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—NH₂;N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl); orS(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₆-cycloalkyl; 3 to 7 membered heterocyclyl;O—C₃₋₆-cycloalkyl or O-(3 to 7 membered heterocyclyl);R⁹ represents H, C₁₋₁₀-alkyl, branched or unbranched, unsubstituted ormono- or poly-substituted; C₃₋₁₀-cycloalkyl or 3 to 10 memberedheterocyclyl, in each case unsubstituted or mono- or poly-substitutedand in each case optionally connected via a C₁₋₈-alkylene group,branched or unbranched, which in turn may be unsubstituted or mono- orpolysubstituted;R¹⁰ represents H, C₁₋₁₀-alkyl; C₃₋₁₀-cycloalkyl, 3 to 10 memberedheterocyclyl or heteroaryl, optionally connected via a C₁₋₈-alkylenegroup, branched or unbranched, which in turn may be unsubstituted ormono- or polysubstituted; orR⁹ and R¹⁰ together with the nitrogen atom connecting them form a 3 to10 membered heterocyclyl;wherein in each case said C₁₋₆-alkyl and C₁₋₁₀-alkyl may be branched orunbranched; unsubstituted or mono- or polysubstituted; andwherein in each case said C₃₋₆-cycloalkyl, 3 to 7 membered heterocyclyl,C₃₋₁₀-cycloalkyl, 3 to 10 membered heterocyclyl or heteroaryl may beunsubstituted or mono- or polysubstituted;optionally in the form of a single stereoisomer or a mixture ofstereoisomers, in the form of the free compound and/or a physiologicallyacceptable salt and/or a physiologically acceptable solvate thereof.

DETAILED DESCRIPTION

The term “single stereoisomer” preferably means in the sense of thepresent invention an individual enantiomer or diastereomer. The term“mixture of stereoisomers” means in the sense of this invention theracemate and mixtures of enantiomers and/or diastereomers in any mixingratio.

The term “physiologically acceptable salt” preferably comprises in thesense of this invention a salt of at least one compound according to thepresent invention and at least one physiologically acceptable acid orbase.

A physiologically acceptable salt of at least one compound according tothe present invention and at least one physiologically acceptable acidpreferably refers in the sense of this invention to a salt of at leastone compound according to the present invention with at least oneinorganic or organic acid which is physiologically acceptable—inparticular when used in human beings and/or other mammals.

A physiologically acceptable salt of at least one compound according tothe present invention and at least one physiologically acceptable basepreferably refers in the sense of this invention to a salt of at leastone compound according to the present invention as an anion with atleast one preferably inorganic cation, which is physiologicallyacceptable—in particular when used in human beings and/or other mammals.

The term “physiologically acceptable solvate” preferably comprises inthe sense of this invention an adduct of one compound according to thepresent invention and/or a physiologically acceptable salt of at leastone compound according to the present invention with distinct molecularequivalents of one solvent or more solvents. Examples of physiologicallyacceptable solvents are water, alkanols, esters, ethers or ketones.

The terms “C₁₋₆-alkyl” and “C₁₋₁₀-alkyl” preferably comprise in thesense of this invention acyclic saturated aliphatic hydrocarbonresidues, which can be respectively branched or unbranched and can beunsubstituted or can be mono- or polysubstituted, e.g. mono-, di- ortrisubstituted, and which contain 1 to 6 carbon atoms, i.e. 1, 2, 3, 4,5 or 6 carbon atoms, or 1 to 10, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms, respectively, i.e. C₁₋₆ alkyl and C₁₋₁₀ alkyl. PreferredC₁₋₆-alkyl groups are selected from the group consisting of methyl,ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl,n-pentyl, isopentyl, neopentyl, and n-hexyl. Preferred C₁₋₁₀-alkylresidues are selected from the group consisting of methyl, ethyl,n-propyl, 2-propyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl,n-decanyl and isooctyl.

In relation to the terms “C₁₋₄-alkyl” and “C₁₋₁₀-alkyl”, the term“monosubstituted” or “polysubstituted” such as di- or tri-substitutedrefers in the sense of this invention, with respect to the correspondinggroups, to the single substitution or multiple substitution, e.g.disubstitution or trisubstitution, of one or more hydrogen atoms eachindependently of one another by at least one substituent. The term“polysubstituted” such as di- or tri-substituted with respect topolysubstituted groups such as di- or tri-substituted groups includesthe polysubstitution of these groups either on different or on the sameatoms, for example trisubstituted on the same carbon atom, as in thecase of CF₃ or CH₂CF₃ or at various points, as in the case ofCH(OH)—CH₂CH₂—CHCl₂. The multiple substitution can be carried out usingthe same or using different substituents.

The term “C₃₋₆-cycloalkyl” and “C₃₋₁₀-cycloalkyl” mean for the purposesof this invention cyclic aliphatic hydrocarbons containing 3, 4, 5 or 6carbon atoms and 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, respectively,wherein the hydrocarbons in each case can be saturated or unsaturated(but not aromatic), unsubstituted or mono- or polysubstituted. Thecycloalkyl group can be bound to the respective superordinate generalstructure via any desired and possible ring member of the cycloalkylgroup. The cycloalkyl group can also be condensed with furthersaturated, (partially) unsaturated, (hetero)cyclic, aromatic orheteroaromatic ring systems, i.e. with cycloalkyl, heterocyclyl, aryl orheteroaryl residues, which in each case can in turn be unsubstituted ormono- or polysubstituted. C₃₋₁₀-cycloalkyls can furthermore be singly ormultiply bridged such as, for example, in the case of adamantyl,bicycle-[2.2.1]heptyl or bicyclo[2.2.2]octyl. Preferred C₃₋₁₀-cycloalkylgroups are selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, adamantly, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl,

Preferred C₃₋₆-cycloalkyl groups are selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl andcyclohexenyl. Particularly preferred C₃₋₁₀-cycloalkyl groups andC₃₋₆-cycloalkyl groups are C₃₋₆-cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl, inparticular cyclopropyl.

The terms “3 to 7-membered heterocyclyl” and “3 to 10-memberedheterocyclyl” mean for the purposes of this inventionheterocycloaliphatic saturated or unsaturated (but not aromatic)residues having 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members, and 3 to 10,i.e. 3, 4, 5, 6, 7, 8, 9 or 10 ring members, respectively, in which ineach case at least one, if appropriate also two or three carbon atomsare replaced by a heteroatom or a heteroatom group each selectedindependently of one another from the group consisting of O, S, S(═O),S(═O)₂, N, NH and N(C₁₋₆-alkyl) such as N(CH₃), wherein the ring memberscan be unsubstituted or mono- or polysubstituted. The cycloalkyl groupscan also be condensed with further saturated or (partially) unsaturatedcycloalkyl or heterocyclyl, aromatic or heteroaromatic ring systems,which in each case can in turn be unsubstituted or mono- orpolysubstituted. The heterocyclyl group can be bound to thesuperordinate general structure via any desired and possible ring memberof the heterocycloaliphatic residue if not indicated otherwise.

The term “aryl” means for the purpose of this invention aromatichydrocarbons having 6 to 14, i.e. 6, 7, 8, 9, 10, 11, 12, 13 or 14 ringmembers, preferably having 6 to 10, i.e. 6, 7, 8, 9 or 10 ring members,including phenyls and naphthyls. Each aryl residue can be unsubstitutedor mono- or polysubstituted, wherein the aryl substituents can be thesame or different and in any desired and possible position of the aryl.The aryl can be bound to the superordinate general structure via anydesired and possible ring member of the aryl residue. The aryl residuescan also be condensed with further saturated or (partially) unsaturatedcycloalkyl or heterocyclyl, aromatic or heteroaromatic ring systems,which can in turn be unsubstituted or mono- or polysubstituted. Examplesof condensed aryl residues are benzodioxolanyl and benzodioxanyl.Preferably, aryl is selected from the group consisting of phenyl,1-naphthyl, 2-naphthyl, fluorenyl and anthracenyl, each of which can berespectively unsubstituted or mono- or polysubstituted. A particularlypreferred aryl is phenyl, unsubstituted or mono- or polysubstituted.

The term “heteroaryl” for the purpose of this invention represents a 5-,6-, 8-, 9- or 10-membered cyclic aromatic residue containing at least 1,if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatomsare each selected independently of one another from the group S, N and Oand the heteroaryl residue can be unsubstituted or mono- orpolysubstituted; in the case of substitution on the heteroaryl, thesubstituents can be the same or different and be in any desired andpossible position of the heteroaryl. The binding to the superordinategeneral structure can be carried out via any desired and possible ringmember of the heteroaryl residue if not indicated otherwise. Theheteroaryl can also be part of a bi- or polycyclic system having up to10 ring members, wherein the ring system can be formed with furthersaturated or (partially) unsaturated cycloalkyl or heterocyclyl,aromatic or heteroaromatic ring systems, which can in turn beunsubstituted or mono- or polysubstituted. It is preferable for theheteroaryl residue to be selected from the group consisting ofbenzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl,benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl,quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl,dibenzothienyl, furyl (furanyl), imidazolyl, imidazothiazolyl,indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl,indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl,phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl,4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl,phenazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl,thiadiazolyl and triazinyl.

The term “C₁₋₈-alkylene” means in the sense of this invention a bivalentacyclic saturated, aliphatic hydrocarbon residue, which can be branchedor unbranched and also unsubstituted or mono- or polysubstituted, whichcontain 1 to 8 carbon atoms respectively. Preferred C₁₋₈-alkylene groupsare selected from the group consisting of CH₂, CH₂CH₂, CH(CH₃),CH₂CH₂CH₂, CH(CH₃)CH₂, CH(CH₂CH₃), CH₂(CH₂)₂CH₂, CH(CH₃)CH₂CH₂,CH₂CH(CH₃)CH₂, CH(CH₃)CH(CH₃), CH(CH₂CH₃)CH₂, C(CH₃)₂CH₂, CH(CH₂CH₂CH₃)and C(CH₃)(CH₂CH₃).

In relation to the terms “C₁₋₆-alkyl”, “C₁₋₁₀-alkyl”, “C₁₋₆-alkylene”,“C₃₋₆-cycloalkyl”, “C₃₋₁₀-cycloalkyl”, “3 to 7-membered heterocyclyl”and “3 to 10-membered heterocyclyl”, the term “mono- or polysubstituted”refers in the sense of this invention, with respect to the correspondingresidues or groups, to the single substitution or multiple substitution,e.g. disubstitution, trisubstitution, tetrasubstitution, orpentasubstitution, of one or more hydrogen atoms each independently ofone another by at least one substituent selected from the groupconsisting of F; Cl; Br; I; NO₂; CN; ═O; ═NH; ═N(OH); ═N(O—C₁₋₆-alkyl);CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; C₁₋₆-alkyl; (C₁₋₈-alkylene)-OH; C(═O)—H;C(═O)—C₁₋₆-alkyl; C(═O)—OH; C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH);C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂; C(═N—OH)—H;C(═N—OH)—C₁₋₆-alkyl; C(═N—O—C₁₋₆-alkyl)-H;C(═N—O—C₁₋₆-alkyl)-C₁₋₆-alkyl; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C₁₋₆-alkyl; O—(C₁₋₈-alkylene)-OH; O—(C₁₋₈-alkylene)-O—C₁₋₆-alkyl;O—C(═O)—C₁₋₆-alkyl; O—C(═O)—O—C₁₋₆-alkyl; O—(C═O)—N(H)(C₁₋₆-alkyl);O—C(═O)—N(C₁₋₆-alkyl)₂; O—S(═O)₂—C₁₋₆-alkyl; O—S(═O)₂—OH;O—S(═O)₂—O—C₁₋₆-alkyl; O—S(═O)₂—NH₂; O—S(═O)₂—N(H)(C₁₋₆-alkyl);O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂; N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂;N(H)—C(═O)—C₁₋₆-alkyl; N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)(C₁₋₆-alkyl); N(H)—C(═O)—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—NH₂; N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂—OH;N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl); N(H)—S(═O)₂—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—OH; N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—NH₂;N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₆-cycloalkyl or 3 to 7 membered heterocyclyl.The term “polysubstituted” with respect to polysubstituted residues andgroups includes the polysubstitution of these residues and groups eitheron different or on the same atoms, for example trisubstituted on thesame carbon atom, as in the case of CF₃, CH₂CF₃ or1,1-difluorocyclohexyl, or at various points, as in the case ofCH(OH)—CHCl₂ or 1-chloro-3-fluorocyclohexyl. A substituent can ifappropriate for its part in turn be mono- or polysubstituted. Themultiple substitution can be carried out using the same or usingdifferent substituents.

Preferred substituents of “C₁₋₆-alkyl”, “C₁₋₁₀-alkyl” and“C₁₋₆-alkylene” are selected from the group consisting of F; Cl; Br; I;NO₂; CF₃; CN; ═O; ═NH; C₁₋₆-alkyl; (C₁₋₈-alkylene)-OH; C(═O)—H;C(═O)—C₁₋₆-alkyl; C(═O)—OH; C(═O)—O—C₁₋₆-alkyl; C(═O)—NH₂;C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂; OH; O—C₁₋₆-alkyl;O—C(═O)—C₁₋₆-alkyl; O—(C₁₋₈-alkylene)-OH;O—(C₁₋₈-alkylene)-O—C₁₋₆-alkyl; OCF₃; NH₂; N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl; N(H)—S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl; N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)(C₁₋₆-alkyl); N(H)—C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl); N(H)—S(═O)₂—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—NH₂; N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; S—C₁₋₆-alkyl; S(═O)₂C₁₋₆-alkyl; S(═O)₂OH; S(═O)₂O—C₁₋₆-alkyl and S(═O)₂—NH₂;S(═O)₂—N(H)(C₁₋₆-alkyl); and S(═O)₂—N(C₁₋₆-alkyl)₂.

Particularly preferred substituents of “C₁₋₆-alkyl”, “C₁₋₁₀-alkyl” and“C₁₋₆-alkylene” are selected from the group consisting of F; Cl; Br; I;CF₃; C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂; OH;O—C₁₋₆-alkyl; O—(C₁₋₈-alkylene)-OH; O—(C₁₋₈-alkylene)-O—C₁₋₆-alkyl; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(H)—S(═O)₂—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;N(H)—S(═O)₂—NH₂; SH; S—C₁₋₆-alkyl; S(═O)₂ C₁₋₆-alkyl andS(═O)₂—N(H)(C₁₋₆-alkyl).

Preferred substituents of “C₃₋₆-cycloalkyl”, “C₃₋₁₀-cycloalkyl”, “3 to7-membered heterocyclyl” and “3 to 10-membered heterocyclyl” areselected from the group consisting of F; Cl; Br; I; NO₂; CF₃; CN; ═O;C₁₋₆-alkyl; C₃₋₆-cycloalkyl or 3 to 7 membered heterocyclyl;C₃₋₆-cycloalkyl or 3 to 7 membered heterocyclyl, each bridged via aC₁₋₈-alkylene; CHO; C(═O)—C₁₋₆-alkyl; CO₂H; C(═O)O—C₁₋₆-alkyl; CONH₂;C(═O)NH—C₁₋₆-alkyl; C(═O)N(C₁₋₆-alkyl)₂; OH; O—C₁₋₆-alkyl; OCF₃;O—(C₁₋₈-alkylene)-OH; O—(C₁₋₈-alkylene)-O—C₁₋₆-alkyl;O—C(═O)—C₁₋₆-alkyl; NH₂; NH—C₁₋₆-alkyl; N(C₁₋₆-alkyl)₂;NH—C(═O)—C₁₋₆-alkyl; SH; S—C₁₋₆-alkyl; SCF₃; S(═O)₂—C₁₋₆-alkyl;S(═O)₂OH; S(═O)₂O—C₁₋₆-alkyl and S(═O)₂—NH—C₁₋₆-alkyl.

In relation to the terms “aryl” and “heteroaryl”, the term “mono- orpolysubstituted” refers in the sense of this invention, with respect tothe corresponding residues or groups, to the single substitution ormultiple substitution, e.g. disubstitution, trisubstitution,tetrasubstitution, or pentasubstitution, of one or more hydrogen atomseach independently of one another by at least one substituent selectedfrom the group consisting of F; Cl; Br; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl;CFCl₂; C₁₋₆-alkyl; C₃₋₆-cycloalkyl; 3 to 7 membered heterocyclyl; aryl;heteroaryl; aryl, heteroaryl, C₃₋₆-cycloalkyl or 3 to 7 memberedheterocyclyl, each connected via a C₁₋₈-alkylene; C(═O)H;C(═O)—(C₁₋₆-alkyl); C(═O)—(C₃₋₆-cycloalkyl); C(═O)-(3 to 7 memberedheterocyclyl); C(═O)-(aryl); C(═O)-(heteroaryl); C(═O)OH;C(═O)—O(C₁₋₆-alkyl); C(═O)—O(C₃₋₆-cycloalkyl); C(═O)—O (3 to 7 memberedheterocyclyl); C(═O)—O(aryl); C(═O)—O(heteroaryl); C(═O)—NH₂;C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(H)(C₃₋₆-cycloalkyl); C(═O)—N(H)(3 to 7membered heterocycloalkyl); C(═O)—N(H)(aryl); C(═O)—N(H)(heteroaryl);C(═O)—N(C₁₋₆-alkyl)₂; C(═O)—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl);C(═O)—N(C₁₋₆-alkyl)(3 to 7 membered heterocyclyl);C(═O)—N(C₁₋₆-alkyl)(aryl); C(═O)—N(C₁₋₆-alkyl)(heteroaryl); OH; ═O;O—(C₁₋₆-alkyl); O—(C₃₋₆-cycloalkyl); O-(3 to 7 membered heterocyclyl);O-(aryl); O-(heteroaryl); OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C(═O)—(C₁₋₆-alkyl); O—C(═O)—(C₃₋₆-cycloalkyl); O—C(═O)-(3 to 7membered heterocyclyl); O—C(═O)-(aryl); C(═O)-(heteroaryl); O—C(═O)—NH₂;O—C(═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(H)(C₃₋₆-cycloalkyl); O—C(═O)—N(H)(3to 7 membered heterocyclyl); O—C(═O)—N(H)(aryl);O—C(═O)—N(H)(heteroaryl); O—C(═O)—N(C₁₋₆-alkyl)₂;O—C(═O)—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl); O—C(═O)—N(C₁₋₆-alkyl)(3 to 7membered heterocyclyl); O—C(═O)—N(C₁₋₆-alkyl)(aryl);O—C(═O)—N(C₁₋₆-alkyl)(heteroaryl); NH₂; N(H)(C₁₋₆-alkyl);N(H)(C₃₋₆-cycloalkyl); N(H)(3 to 7 membered heterocyclyl); N(H)(aryl);N(H)(heteroaryl); N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl);N(C₁₋₆-alkyl)(3 to 7 membered heterocyclyl); N(C₁₋₆-alkyl) (aryl);N(C₁₋₆-alkyl)(heteroaryl); N(H)—C(═O)—(C₁₋₆-alkyl);N(H)—C(═O)—(C₃₋₆-cycloalkyl); N(H)—C(═O)-(3 to 7 membered heterocyclyl);N(H)—C(═O)-(aryl); N(H)—C(═O)-(heteroaryl);N(C₁₋₆-alkyl)-C(═O)—(C₁₋₆-alkyl); N(C₁₋₆-alkyl)-C(═O)—(C₃₋₆-cycloalkyl);N(C₁₋₆-alkyl)-C(═O)-(3 to 7 membered heterocyclyl);N(C₁₋₆-alkyl)-C(═O)-(aryl); N(C₁₋₆-alkyl)-C(═O)-(heteroaryl);N(H)—S(═O)₂—(C₁₋₆-alkyl); N(H)—S(═O)₂—(C₃₋₆-cycloalkyl); N(H)—S(═O)₂-(3to 7 membered heterocyclyl); N(H)—S(═O)₂-(aryl);N(H)—S(═O)₂-(heteroaryl); N(C₁₋₄-alkyl)-S(═O)₂—(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—(C₃₋₆-cycloalkyl); N(C₁₋₆-alkyl)-S(═O)₂-(3 to 7membered heterocyclyl); N(C₁₋₆-alkyl)-S(═O)₂-(aryl);N(C₁₋₆-alkyl)-S(═O)₂-(heteroaryl); N(H)—C(═O)—O(C₁₋₆-alkyl);N(H)—C(═O)—O(C₃₋₆-cycloalkyl); N(H)—C(═O)—O (3 to 7 memberedheterocyclyl); N(H)—C(═O)—O(aryl); N(H)—C(═O)—O(heteroaryl);N(C₁₋₆-alkyl)-C(═O)—O(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—O(C₃₋₆-cycloalkyl); N(C₁₋₆-alkyl)-C(═O)—O (3 to 7membered heterocyclyl); N(C₁₋₆-alkyl)-C(═O)—O(aryl);N(C₁₋₆-alkyl)-C(═O)—O(heteroaryl); N(H)—C(═O)—NH₂;N(H)—C(═O)—N(H)(C₁₋₆-alkyl); N(H)—C(═O)—N(H)(C₃₋₆-cycloalkyl);N(H)—C(═O)—N(H)(3 to 7 membered heterocyclyl); N(H)—C(═O)—N(H)(aryl);N(H)—C(═O)—N(H)(heteroaryl); N(C₁₋₆-alkyl)-C(═O)—NH₂;N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(H)(C₃₋₆-cycloalkyl); N(C₁₋₆-alkyl)-C(═O)—N(H)(3 to7 membered heterocyclyl); N(C₁₋₆-alkyl)-C(═O)—N(H)(aryl);N(C₁₋₆-alkyl)-C(═O)—N(H)(heteroaryl); N(H)—C(═O)—N(C₁₋₆-alkyl)₂;N(H)—C(═O)—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl); N(H)—C(═O)—N(C₁₋₆-alkyl)(3 to7 membered heterocyclyl); N(H)—C(═O)—N(C₁₋₆-alkyl)(aryl);N(H)—C(═O)—N(C₁₋₆-alkyl) (heteroaryl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)(3 to 7 membered heterocyclyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)(aryl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl) heteroaryl); SH; S—(C₁₋₆-alkyl);S—(C₃₋₆-cycloalkyl); S-(3 to 7 membered heterocyclyl); S-(aryl);S-(heteroaryl); SCF₃; S(═O)₂OH; S(═O)—(C₁₋₆-alkyl);S(═O)—(C₃₋₆-cycloalkyl); S(═O)-(3 to 7 membered heterocyclyl);S(═O)-(aryl); S(═O)-(heteroaryl); S(═O)₂—(C₁₋₆-alkyl);S(═O)₂—(C₃₋₆-cycloalkyl); S(═O)₂-(3 to 7 membered heterocyclyl);S(═O)₂-(aryl); S(═O)₂-(heteroaryl); S(═O)₂—O(C₁₋₆-alkyl);S(═O)₂—O(C₃₋₆-cycloalkyl); S(═O)₂—O (3 to 7 membered heterocyclyl);S(═O)₂—O(aryl); S(═O)₂—O(heteroaryl); S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(H)(C₃₋₆-cycloalkyl); S(═O)₂—N(H)(3 to 7 membered heterocyclyl);S(═O)₂—N(H)(aryl); S(═O)₂—N(H)(heteroaryl); S(═O)₂—N(C₁₋₆-alkyl)₂;S(═O)₂—N(C₁₋₆-alkyl)(C₃₋₆-cycloalkyl); S(═O)₂—N(C₁₋₆-alkyl)(3 to 7membered heterocyclyl); S(═O)₂—N(C₁₋₆-alkyl)(aryl) andS(═O)₂—N(C₁₋₆-alkyl)(heteroaryl).

Preferred substituents of “aryl” and “heteroaryl” are selected from thegroup consisting of F; Cl; Br; NO₂; CN; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂;C₁₋₆-alkyl; aryl; heteroaryl; C₃₋₆-cycloalkyl; 3 to 6 memberedheterocyclyl; aryl, heteroaryl, C₃₋₆-cycloalkyl or 3 to 6 memberedheterocycloaliphatic, each connected via a C₁₋₈-alkylene; C(═O)—H;C(═O)—C₁₋₆-alkyl; C(═O)aryl; C(═O)heteroaryl; C(═O)—OH;C(═O)—O—C₁₋₆-alkyl; C(═O)O-aryl; C(═O)O-heteroaryl; CO—NH₂;C(═O)—N(H)C₁₋₆-alkyl; C(═O)—N(C₁₋₆-alkyl)₂; C(═O)NH-aryl; C(═O)N(aryl)₂;C(═O)NH-heteroaryl; C(═O)—N(heteroaryl)₂; C(═O)N(C₁₋₆-alkyl)(aryl);C(═O)N(C₁₋₆-alkyl)(heteroaryl); C(═O)N(heteroaryl)(aryl); OH; OCF₃;OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂; O—C₁₋₆-alkyl; O-benzyl; O-aryl;O-heteroaryl; O—C(═O)—C₁₋₆-alkyl; O—C(═O)aryl; O—C(═O)heteroaryl;O—C(═O)—O—C₁₋₆-alkyl; O—(C═O)—N(H)C₁₋₆-alkyl; O—C(═O)—N(C₁₋₆-alkyl)₂;O—S(═O)₂—C₁₋₆-alkyl; O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₆-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)C₁₋₆-alkyl; O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂; N(H)C₁₋₆-alkyl;N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl; N(H)—C(═O)-aryl;N(H)—C(═O)-heteroaryl; N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)C(═O)—NH₂;N(H)—C(═O)—N(H)C₁₋₆-alkyl; N(H)—C(═O)—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-C(═O)C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl;N(C₁₋₆-alkyl)C(═O)—NH₂; N(C₁₋₆-alkyl)-C(═O)—N(H)C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂—OH;N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂;N(H)S(═O)₂—N(H)C₁₋₆-alkyl; N(H)—S(═O)₂—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—OH; N(C₁₋₆-alkyl)-S(═O)₂(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—O(C₁₋₆-alkyl); N(C₁₋₆-alkyl)-S(═O)₂—NH₂;N(C₁₋₆-alkyl)-S(═O)₂—N(H)C₁₋₆-alkyl; N(C₁₋₆-alkyl)S(═O)₂—N(C₁₋₆-alkyl)₂;SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl; SCFCl₂; S—C₁₋₆-alkyl; S-benzyl; S-aryl;Sheteroaryl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂-aryl;S(═O)₂-heteroaryl; S(═O)₂—OH; S(═O)₂—OC₁₋₆-alkyl; S(═O)₂O-aryl;S(═O)₂O-heteroaryl; S(═O)₂—NH₂; S(═O)₂—N(H)C₁₋₆-alkyl, S(═O)₂—N(H)-aryl;S(═O)₂—N(H)-heteroaryl and S(═O)₂—N(C₁₋₆-alkyl)₂.

More preferred substituents of “aryl” and “heteroaryl” are selected fromthe group consisting of F; Cl; CF₃; CN; C₁₋₆-alkyl; C(═O)—OH;C(═O)—O—C₁₋₆-alkyl; CO—NH₂; C(═O)—N(H)C₁₋₆-alkyl; C(═O)—N(C₁₋₆-alkyl)₂;OH; O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; OCF₃; OCHF₂; OCH₂F; NH₂;N(H)C₁₋₆-alkyl; N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)C₁₋₆-alkyl; N(H)—S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂(C₁₋₆-alkyl); N(H)C(═O)NH₂;N(H)C(═O)—N(H)C₁₋₆-alkyl; N(H)—C(═O)—N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-C(═O)—NH₂; N(C₁₋₆-alkyl)C(═O)—N(H)C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; S(═O)₂C₁₋₆-alkyl; S(═O)₂—NH₂;S(═O)₂—N(H)C₁₋₆-alkyl and S(═O)₂—N(C₁₋₆-alkyl)₂.

The compounds according to the invention are defined by substituents,for example by R¹, R² and R³ (1^(st) generation substituents) which arefor their part if appropriate themselves substituted (2^(nd) generationsubstituents). Depending on the definition, these substituents of thesubstituents can for their part be resubstituted (3^(rd) generationsubstituents). If, for example, R¹=a C₁₋₆-alkyl (1^(st) generationsubstituent), then the C₁₋₆-alkyl can for its part be substituted, forexample with a NH— C₁₋₆-alkyl (2^(nd) generation substituent). Thisproduces the functional group R¹═(C₁₋₆-alkyl-NH—C₁₋₆-alkyl). TheNH—C₁₋₆-alkyl can then for its part be resubstituted, for example withCl (3^(rd) generation substituent). Overall, this produces thefunctional group R¹═C₁₋₆-alkyl-NH—C₁₋₆-alkyl, wherein the C₁₋₆-alkyl ofthe NH—C₁₋₆-alkyl is substituted by CI. However, in a preferredembodiment, the 3^(rd) generation substituents may not be resubstituted,i.e. there are then no 4^(th) generation substituents. If a residueoccurs multiply within a molecule, then this residue can haverespectively different meanings for various substituents: if, forexample, both R¹ and R² denote a 3 to 10 membered heterocyclyl, then the3 to 10 membered heterocyclyl can e.g. represent morpholinyl for R¹ andcan represent piperazinyl for R².

Within the scope of the present invention, the symbols

or

used in the formulae denotes a link of a corresponding residue to therespective superordinate general structure.

In one embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that

R¹, R² and R³ are each independently selected from the group consistingof H; F; Cl; Br; I; NO₂; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂;C(═O)—H; C(═O)—C₁₋₆-alkyl; C(═O)—OH; C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH);C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂; C(═N—OH)—H;C(═N—OH)—C₁₋₆-alkyl; C(═N—O—C₁₋₆-alkyl)-H;C(═N—O—C₁₋₆-alkyl)-C₁₋₆-alkyl; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; O—C(═O)—O—C₁₋₆-alkyl;O—(C═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(C₁₋₆-alkyl)₂; O—S(═O)₂—C₁₋₆-alkyl;O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₆-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)(C₁₋₆-alkyl); O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)(C₁₋₆-alkyl);N(H)—C(═O)—N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—NH₂;N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂OH;N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl); N(H)—S(═O)₂N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—OH; N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—NH₂;N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆-alkyl)₂, C₃₋₆-cycloalkyl or 3 to 7 membered heterocyclyl,wherein in each case said C₁₋₆-alkyl may be branched or unbranched andmay be unsubstituted or mono- or polysubstituted;and wherein in each case said C₃₋₆-cycloalkyl or 3 to 7 memberedheterocyclyl may be unsubstituted or mono- or polysubstituted.

Preferably, R¹, R² and R³ are each independently selected from the groupconsisting of H; F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH; OCF₃;O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; NH₂; N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂;SCF₃; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆alkyl)₂, wherein in each case C₁₋₆-alkyl may be branched orunbranched, or C₃₋₆-cycloalkyl, unsubstituted or mono- orpolysubstituted.

Still preferably, R¹, R² and R³ are each independently selected from thegroup consisting of H; F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH; OCF₃;OCF₂H; OCFH₂; O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; NH₂; N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)₂; SCF₃; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl); orS(═O)₂—N(C₁₋₆-alkyl)₂, wherein in each case C₁₋₆-alkyl may be branchedor unbranched.

More preferably, R¹, R² and R³ are independently selected from the groupconsisting of H, F, Cl, CFH₂, CF₂H, CF₃, CN, CH₂—OCH₃, S(═O)₂—CH₃, OCF₃,CH₃, O—CH₃, O—CH₂CH₃ and N(CH₃)₂.

Even more preferably, R¹, R² and R³ are independently selected from thegroup consisting of H, F, Cl, CN, CFH₂, CF₂H, CF₃, OCF₃, CH₃,S(═O)₂—CH₃, OCH₃, and OCH₂CH₃.

Particularly preferred, R¹, R² and R³ are independently selected fromthe group consisting of H, F, Cl, CF₃, CH₃ and OCH₃. In one particularpreferred embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that R¹, R² and R³denote H.

In another particular preferred embodiment of the first aspect of theinvention, the compound according to general formula (I) ischaracterized in that at least one of R¹, R² and R³ is ≠H.

In one embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that n represents 1or 2, preferably n represents 1.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that m represents0.

In one particular preferred embodiment of the first aspect of theinvention, the compound according to general formula (I) ischaracterized in that n represents 1 and m represents 0.

Yet another embodiment of the first aspect of the invention is thecompound according to general formula (I) which is characterized in that

n represents 1 and m represents 0; andR¹, R² and R³ are each independently of one another selected from thegroup consisting of H; F; Cl; CN; CF₃; CF₂H; CFH₂; OH; OCF₃; OCF₂H;OCFH₂; O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; NH₂; N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)₂; SCF₃; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl) orS(═O)₂—N(C₁₋₆-alkyl)₂,wherein in each case C₁₋₆-alkyl may be branched or unbranched.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that R⁴ representsCH₂F, CHF₂ or CF₃. Preferably, R⁴ represents CHF₂ or CF₃.

A particularly preferred compound according to formula (I) ischaracterized in that R⁴ represents CF₃.

Another particularly preferred compound according to formula (I) ischaracterized in that R⁴ represents CHF₂.

In a further embodiment of the first aspect of the invention, thecompound according to general formula (I) is characterized in that R⁵represents H, C₁₋₆-alkyl, branched or unbranched, unsubstituted or mono-or poly-substituted, C₃₋₆-cycloalkyl or 3 to 7 membered heterocyclyl, ineach case unsubstituted or mono- or polysubstituted; OH; O—C₁₋₆-alkyl;NH₂; N(H)—C₁₋₆-alkyl; N(—C₁₋₆-alkyl)₂ or SO₂(—C₁₋₆-alkyl), wherein ineach case C₁₋₆-alkyl may be branched or unbranched and may beunsubstituted or mono- or polysubstituted.

Preferably, R⁵ is selected from the group consisting of H, methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,cyclopropyl, methoxy, ethoxy, methylsulfonyl, 2-oxetyl, 3-oxetyl,2-tetrahydrofuranyl and 3-tetrahydrofuranyl.

More preferably, R⁵ is selected from the group consisting of H, methyl,ethyl, iso-propyl and cyclopropyl. Even more preferably, R⁵ represents Hor methyl.

In a particularly preferred embodiment of the invention, the compoundaccording to general formula (I) is characterized in that R⁵ representsmethyl (CH₃). In another particularly preferred embodiment of theinvention, the compound according to general formula (I) ischaracterized in that R⁵ represents H.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is selected from a compound accordingto general formula (Ia) or from a compound according to general formula(Ib),

wherein Het, R⁹ and R¹⁰ are defined as above.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that Het isselected from the group consisting of

pyrrol, furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl,isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, indolyl, benzofuranyl, benzothienyl, indazolyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl,isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl,1,8-naphthyridinyl, 2,3-naphthyridinyl, 2,6-naphthyridinyl and2,7-naphthyridinyl, each substituted by zero or one or two or threesubstituents of the group consisting of R⁶, R⁷ and R⁸.

Preferably, Het is selected from the group consisting of pyrrol,thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl,pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, each substituted byzero or one or two or three substituents of the group consisting of R⁶,R⁷ and R⁸.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that R⁶, R⁷ and R⁸are independently selected from the group consisting of F; Cl; CN;C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH; OCF₃; OCF₂H; OCFH₂; O—C₁₋₆-alkyl;O—C(═O)—C₁₋₆-alkyl; NH₂; N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; SCF₃;S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH; S(═O)₂—O—C₁₋₆-alkyl;S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl); S(═O)₂—N(C₁₋₆-alkyl)₂;C₃₋₆-cycloalkyl or O—C₃₋₆-cycloalkyl,

wherein in each case said C₁₋₆-alkyl may be branched or unbranched andwherein in each case said C₃₋₆-cycloalkyl may be unsubstituted or mono-or polysubstituted.

Preferably, R⁶, R⁷ and R⁸ are each independently selected from the groupconsisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH; OCF₃; OCF₂H;OCFH₂; O—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; cyclopropyland O-cyclopropyl.

More preferably, Het is selected from the group consisting of pyrrol,thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl,pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, each substituted byzero or one or two or three substituents of the group consisting of R⁶,R⁷ and R⁸,

wherein R⁶, R⁷ and R⁸ are each independently of one another selectedfrom the group consisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH;OCF₃; OCF₂H; OCFH₂; O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; SCF₃; S(═O)—C₁₋₆-alkyl;S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH; S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂;S(═O)₂—N(H)(C₁₋₆-alkyl); S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₆-cycloalkyl orO—C₃₋₆-cycloalkyl,wherein in each case said C₁₋₆-alkyl may be branched or unbranched andwherein in each case said C₃₋₆-cycloalkyl may be unsubstituted or mono-or polysubstituted.

Even more preferably, Het is selected from the group consisting ofpyrrol, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl,pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, each substituted byzero or one or two or three substituents of the group consisting of R⁶,R⁷ and R⁸,

wherein R⁶, R⁷ and R⁸ are each independently of one another selectedfrom the group consisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH;OCF₃; OCF₂H; OCFH₂; O—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl;cyclopropyl and O-cyclopropyl.

Yet more preferably, Het is selected from the group consisting of

pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl,thiophen-2-yl, thiophen-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl,imidazol-2-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,each substituted by zero or one or two substituents of the groupconsisting of R⁶ and R⁷, wherein R⁶ and R⁷ are each independently of oneanother selected from the group consisting of F; Cl; CN; CF₃; CH₃; OH;OCF₃, OCH₃, S(O)CH₃ and S(O)₂CH₃.

Particularly preferred, Het is selected from the group consisting of6-hydroxy-pyridin-3-yl, 3-fluoro-5-(trifluoromethyl)-pyridin-2-yl,6-cyano-4-methyl-pyridin-3-yl, 6-chloro-4-methyl-pyridin-3-yl,6-methoxy-4-methyl-pyridin-3-yl, 2-cyano-4-methyl-pyridin-5-yl,pyridin-2-yl, 3-fluoro-pyridin-2-yl, 4-fluoro-pyridin-2-yl,5-fluoro-pyridin-2-yl, 6-fluoro-pyridin-2-yl, 3-chloro-pyridin-2-yl,4-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl, 6-chloro-pyridin-2-yl,3-cyano-pyridin-2-yl, 4-cyano-pyridin-2-yl, 5-cyano-pyridin-2-yl,6-cyano-pyridin-2-yl, 3-methoxy-pyridin-2-yl, 4-methoxy-pyridin-2-yl,5-methoxy-pyridin-2-yl, 6-methoxy-pyridin-2-yl, 3-methyl-pyridin-2-yl,4-methyl-pyridin-2-yl, 5-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl,3-trifluoromethyl-pyridin-2-yl, 4-trifluoromethyl-pyridin-2-yl,5-trifluoromethyl-pyridin-2-yl, 6-trifluoromethyl-pyridin-2-yl,4-methylsulfinyl-pyridin-2-yl, 4-chloro-6-methylsulfinyl-pyridin-2-yl,pyridin-3-yl, 2-fluoro-pyridin-3-yl, 4-fluoro-pyridin-3-yl,5-fluoro-pyridin-3-yl, 6-fluoro-pyridin-3-yl, 2-chloro-pyridin-3-yl,4-chloro-pyridin-3-yl, 5-chloro-pyridin-3-yl, 6-chloro-pyridin-3-yl,2-cyano-pyridin-3-yl, 4-cyano-pyridin-3-yl, 5-cyano-pyridin-3-yl,6-cyano-pyridin-3-yl, 2-methoxy-pyridin-3-yl, 4-methoxy-pyridin-3-yl,5-methoxy-pyridin-3-yl, 6-methoxy-pyridin-3-yl, 2-methyl-pyridin-3-yl,4-methyl-pyridin-3-yl, 5-methyl-pyridin-3-yl, 6-methyl-pyridin-3-yl,2-trifluoromethyl-pyridin-3-yl, 4-trifluoromethyl-pyridin-3-yl,5-trifluoromethyl-pyridin-3-yl, 6-trifluoromethyl-pyridin-3-yl,pyridin-4-yl, 2-fluoro-pyridin-4-yl, 3-fluoro-pyridin-4-yl,2-chloro-pyridin-4-yl, 3-chloro-pyridin-4-yl, 2-cyano-pyridin-4-yl,3-cyano-pyridin-4-yl, 2-methoxy-pyridin-4-yl, 3-methoxy-pyridin-4-yl,2-methyl-pyridin-4-yl, 3-methyl-pyridin-4-yl,2-trifluoromethyl-pyridin-4-yl, 3-trifluoromethyl-pyridin-4-yl,pyrimidin-2-yl, 4-fluoro-pyrimidin-2-yl, 4-chloro-pyrimidin-2-yl,5-fluoro-pyrimidin-2-yl, 5-chloro-pyrimidin-2-yl,4-methoxy-pyrimidin-2-yl, 4-methyl-pyrimidin-2-yl,5-methoxy-pyrimidin-2-yl, 5-methyl-pyrimidin-2-yl,4-trifluoromethyl-pyrimidin-2-yl, 4-cyano-pyrimidin-2-yl,5-trifluoromethyl-pyrimidin-2-yl, 5-cyano-pyrimidin-2-yl,pyrimidin-4-yl, 2-fluoro-pyrimidin-4-yl, 2-chloro-pyrimidin-4-yl,5-fluoro-pyrimidin-4-yl, 5-chloro-pyrimidin-4-yl,6-fluoro-pyrimidin-4-yl, 6-chloro-pyrimidin-4-yl,2-trifluoromethyl-pyrimidin-4-yl, 2-cyano-pyrimidin-4-yl,5-trifluoromethyl-pyrimidin-4-yl, 5-cyano-pyrimidin-4-yl,6-trifluoromethyl-pyrimidin-4-yl, 6-cyano-pyrimidin-4-yl,2-methyl-pyrimidin-4-yl, 2-methoxy-pyrimidin-4-yl,5-methyl-pyrimidin-4-yl, 5-methoxy-pyrimidin-4-yl,6-methyl-pyrimidin-4-yl, 6-methoxy-pyrimidin-4-yl, pyrimidin-5-yl,2-fluoro-pyrimidin-5-yl, 2-chloro-pyrimidin-5-yl,4-fluoro-pyrimidin-5-yl, 4-chloro-pyrimidin-5-yl,2-methyl-pyrimidin-5-yl, 2-methoxy-pyrimidin-5-yl,4-methyl-pyrimidin-5-yl, 4-methoxy-pyrimidin-5-yl,2-trifluoromethyl-pyrimidin-5-yl, 2-cyano-pyrimidin-5-yl,4-trifluoromethyl-pyrimidin-5-yl, 4-cyano-pyrimidin-5-yl, pyrazin-2-yl,2-methoxy-pyrazin-2-yl, 5-methoxy-pyrazin-2-yl, 6-methoxy-pyrazin-2-yl,2-methyl-pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 6-methyl-pyrazin-2-yl,2-fluoro-pyrazin-2-yl, 5-fluoro-pyrazin-2-yl, 6-fluoro-pyrazin-2-yl,2-chloro-pyrazin-2-yl, 5-chloro-pyrazin-2-yl, 6-chloro-pyrazin-2-yl,2-trifluoromethyl-pyrazin-2-yl, 5-trifluoromethyl-pyrazin-2-yl,6-trifluoromethyl-pyrazin-2-yl, 2-cyano-pyrazin-2-yl,5-cyano-pyrazin-2-yl, 6-cyano-pyrazin-2-yl, pyridazin-3-yl,4-methoxy-pyridazin-3-yl, 5-methoxy-pyridazin-3-yl,6-methoxy-pyridazin-3-yl, 4-methyl-pyridazin-3-yl,5-methyl-pyridazin-3-yl, 6-methyl-pyridazin-3-yl,4-fluoro-pyridazin-3-yl, 5-fluoro-pyridazin-3-yl,6-fluoro-pyridazin-3-yl, 4-chloro-pyridazin-3-yl,5-chloro-pyridazin-3-yl, 6-chloro-pyridazin-3-yl,4-trifluoromethyl-pyridazin-3-yl, 5-trifluoromethyl-pyridazin-3-yl,6-trifluoromethyl-pyridazin-3-yl, 4-cyano-pyridazin-3-yl,5-cyano-pyridazin-3-yl, 6-cyano-pyridazin-3-yl, pyridazin-4-yl,3-methoxy-pyridazin-4-yl, 5-methoxy-pyridazin-4-yl,6-methoxy-pyridazin-4-yl, 3-methyl-pyridazin-4-yl,5-methyl-pyridazin-4-yl, 6-methyl-pyridazin-4-yl,3-fluoro-pyridazin-4-yl, 5-fluoro-pyridazin-4-yl,6-fluoro-pyridazin-4-yl, 3-chloro-pyridazin-4-yl,5-chloro-pyridazin-4-yl, 6-chloro-pyridazin-4-yl,3-trifluoromethyl-pyridazin-4-yl, 5-trifluoromethyl-pyridazin-4-yl,6-trifluoromethyl-pyridazin-4-yl, 3-cyano-pyridazin-4-yl,5-cyano-pyridazin-4-yl, 6-cyano-pyridazin-4-yl,3,5-dimethyl-isoxazol-4-yl, 3,5-di-(trifluoromethyl)-isoxazol-4-yl,1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl,5-trifluoro-methyl-1-methyl-1H-pyrazol-4-yl,3-trifluoromethyl-1-methyl-1H-pyrazol-4-yl,1,5-di-methyl-1H-pyrazol-4-yl, 1,3-dimethyl-1H-pyrazol-4-yl,1,3,5-trimethyl-1H-pyrazol-4-yl, 1H-pyrazol-3-yl,1-methyl-1H-pyrazol-3-yl, 5-trifluoromethyl-1-methyl-1H-pyrazol-3-yl,4-trifluoromethyl-1-methyl-1H-pyrazol-3-yl,1,5-dimethyl-1H-pyrazol-3-yl, 1,4-dimethyl-1H-pyrazol-3-yl and1,4,5-trimethyl-1H-pyrazol-3-yl.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that

R⁹ represents H orC₁₋₆-alkyl, branched or unbranched and unsubstituted or substituted with1, 2, 3, 4 or 5 substituents independently selected from the groupconsisting of OH, ═O, O—C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl;N(H)—C(═O)—C₁₋₆-alkyl, and N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; orC₃₋₆-cycloalkyl, unsubstituted or substituted with 1, 2, 3, 4 or 5substituents independently selected from the group consisting of F, Cl,CF₃, ═O, OCF₃; C₁₋₈-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl,S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, N(H)—S(═O)—C₁₋₆-alkyl,N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl, N(H)—S(═O)₂—C₁₋₆-alkyl,N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, C(═O)—NH₂, C(═O)—N(H)(C₁₋₆-alkyl),C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—C₁₋₆-alkyl, andN(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; wherein said C₃₋₆-cycloalkyl residue isoptionally connected via a C₁₋₈-alkylene group, which in turn may bebranched or unbranched and unsubstituted or substituted with 1, 2, 3, 4or 5 substituents independently selected from the group consisting of F,Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl and C₁₋₈-alkylen-OH; or3 to 7 membered heterocyclyl, which is unsubstituted or substituted with1, 2, 3, 4 or 5 substituents independently selected from the groupconsisting of F, Cl, CF₃, ═O, OCF₃; C₁₋₈-alkylen-OH, C₁₋₆-alkyl, OH,O—C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl;N(H)—C(═O)—C₁₋₆-alkyl, and N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl, wherein said3 to 7 membered heterocyclyl is optionally connected via a C₁₋₈-alkylenegroup, which in turn may be branched or unbranched and unsubstituted orsubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom the group consisting of F, Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl andC₁₋₈-alkylen-OH.

More preferably,

R⁹ represents represents H orC₁₋₆-alkyl, branched or unbranched and unsubstituted or substituted with1, 2, 3, 4 or 5 substituents independently selected from the groupconsisting of OH, ═O, O—C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl;N(H)—C(═O)—C₁₋₆-alkyl, and N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl.

Still more preferably, R⁹ represents represents H or C₁₋₆-alkyl.Particularly preferred, R⁹ represents represents H, methyl, ethyl,iso-propyl or n-propyl.

In a preferred embodiment of the first aspect of the present invention,R⁹ denotes methyl. In another preferred embodiment of the first aspectof the present invention, R⁹ represents H.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that

R¹⁰ wherein said C₃₋₁₀-cycloalkyl, 3 to 10 membered heterocyclyl orheteroaryl in each case may be unsubstituted or mono- orpoly-substituted and wherein said C₃₋₁₀-cycloalkyl, 3 to 10 memberedheterocyclyl or heteroaryl may be in each case connected via aC₁₋₈-alkylene group, which in turn may be branched or unbranched and maybe unsubstituted or mono- or polysubstituted.

Preferably, R¹⁰ represents

H or

C₁₋₆-alkyl, branched or unbranched and unsubstituted or substituted with1, 2, 3, 4 or 5 substituents independently selected from the groupconsisting of F, Cl, CF₃, CN, OH, ═O, OCF₃, O—C₁₋₆-alkyl,O—(C═O)C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂,S(═O)₂—N(H)C₁₋₆-alkyl, S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, N(H)—C(═O)—NH₂,N(H)—C(═O)—N(H)(C₁₋₆-alkyl), N(H)—C(═O)—N(C₁₋₆-alkyl)₂,N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂, O—C(═O)—N(H)(C₁₋₆-alkyl),O—C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—NH₂, C(═O)—N(H)(C₁₋₆-alkyl),C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—C₁₋₆-alkyl, andN(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; orC₃₋₆-cycloalkyl, unsubstituted or substituted with 1, 2, 3, 4 or 5substituents independently selected from the group consisting of F, Cl,CN, CF₃, ═O, OCF₃, C₁₋₈-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl,O—(C═O)C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂,S(═O)₂—N(H)C₁₋₆-alkyl, S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl,N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂, O—C(═O)—N(H)(C₁₋₆-alkyl),O—C(═O)—N(C₁₋₆-alkyl)₂, N(H)—C(═O)—NH₂, N(H)—C(═O)—N(H)(C₁₋₆-alkyl),N(H)—C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—NH₂, C(═O)—N(H)(C₁₋₆-alkyl),C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—C₁₋₆-alkyl, andN(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; wherein said C₃₋₆-cycloalkyl isoptionally connected via a C₁₋₈-alkylene group, which in turn may bebranched or unbranched and unsubstituted or substituted with 1, 2, 3, 4or 5 substituents independently selected from the group consisting of F,Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl and C₁₋₈-alkylen-OH; or3 to 7 membered heterocyclyl, which is unsubstituted or substituted with1, 2, 3, 4 or 5 substituents independently from one another selectedfrom the group consisting of F, Cl, CN, CF₃, ═O, OCF₃, C₁₋₆-alkylen-OH,C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, O—(C═O)C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl,S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl,S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl,N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂, O—C(═O)—N(H)(C₁₋₆-alkyl),O—C(═O)—N(C₁₋₆-alkyl)₂, N(H)—C(═O)—NH₂, N(H)—C(═O)—N(H)(C₁₋₆-alkyl),N(H)—C(═O)—N(C₁₋₆-alkyl)₂, (C═O)C₁₋₆-alkyl, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl;N(H)—C(═O)—C₁₋₆-alkyl, and N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; wherein said3 to 7 membered heterocyclyl is optionally connected via a C₁₋₈-alkylenegroup, which in turn may be branched or unbranched and unsubstituted orsubstituted with 1, 2, 3, 4 or 5 substituents independently selectedfrom the group consisting of F, Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl andC₁₋₈-alkylen-OH; orheteroaryl, which is unsubstituted or substituted with 1, 2, 3, 4 or 5substituents selected from the group consisting of F, Cl, CN, CF₃, OCF₃,C₁₋₈-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, O—(C═O)C₁₋₆-alkyl,S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl,S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl,N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂, O—C(═O)—N(H)(C₁₋₆-alkyl),O—C(═O)—N(C₁₋₆-alkyl)₂, N(H)—C(═O)—NH₂, N(H)—C(═O)—N(H)(C₁₋₆-alkyl),N(H)—C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—NH₂, C(═O)—N(H)(C₁₋₆-alkyl),C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—C₁₋₆-alkyl, andN(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl, wherein said heteroaryl residue isoptionally connected via a C₁₋₈-alkylene group, which in turn may bebranched or unbranched and unsubstituted or substituted with 1, 2, 3, 4or 5 substituents independently from one another selected from the groupconsisting of F, CI, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl andC₁₋₈-alkylen-OH.

In another preferred embodiment of the first aspect of the invention,the compound according to general formula (I) is characterized in thatR¹⁰ represents

C₃₋₆-cycloalkyl, which is unsubstituted or substituted with 1, 2, 3, 4or 5 substituents independently from one another selected from the groupconsisting of F, Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₈-alkylen-OHand C₁₋₆-alkyl; or3 to 7 membered heterocyclyl, which contains 1 or 2 heteroatoms orheteroatom groups independently from one another selected from the groupconsisting of O, S, S(═O), S(═O)₂, NH and N—C₁₋₆-alkyl, and which isunsubstituted or substituted with 1, 2, 3, 4 or 5 substituentsindependently from one another selected from the group consisting of F,Cl, CF₃, OCF₃, CN, C₁₋₆-alkyl, C₁₋₈-alkylen-OH and O—C₁₋₆-alkyl; orheteroaryl, which contains at least one nitrogen atom and which isunsubstituted or substituted with 1, 2 or 3 substituents independentlyfrom one another selected from the group consisting of F, Cl, CN, CF₃,OCF₃, C₁₋₈-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,S(═O)₂—NH₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, O—C(═O)—NH₂, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; ora part structure of general formula SF-III

whereinx represents 0, 1 or 2; y represents 0, 1 or 2; z represents 0, 1 or 2;

-   -   on the condition that the sum of x, y and z is 1, 2, 3, 4, 5 or        6;        R¹¹ and R¹² are independently from one another selected from H        or C₁₋₆-alkyl; or        R¹¹ and R¹² together with the carbon atom connecting them form a        C₃₋₆-cycloalkyl or a 3 to 7 membered heterocyclyl, which        contains 1 or 2 heteroatoms or heteroatom groups independently        from one another selected from the group consisting of O, S,        S(═O), S(═O)₂, NH and N—C₁₋₆-alkyl, wherein said C₃₋₆-cycloalkyl        or 3 to 7 membered heterocyclyl may be unsubstituted or        substituted with 1, 2, 3, 4 or 5 substituents independently from        one another selected from the group consisting of F, Cl, CF₃,        OCF₃, CN, C₁₋₆-alkyl and O—C₁₋₆-alkyl;        R¹³ is selected from the group consisting of        H, F, Cl, CN, CF₃, OCF₃, C₁₋₈-alkylen-OH, OH, O—C₁₋₆-alkyl,        O—(C═O)C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,        S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl, S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂,        NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, N(H)—C(═O)—C₁₋₆-alkyl,        N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl, N(H)—S(═O)—C₁₋₆-alkyl,        N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl, N(H)—S(═O)₂—C₁₋₆-alkyl,        N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, C(═O)—NH₂,        C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂,        C(═O)—O—C₁₋₆-alkyl, N(H)—C(═O)—NH₂, N(H)—C(═O)—N(H)(C₁₋₆-alkyl),        N(H)—C(═O)—N(C₁₋₆-alkyl)₂, N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂,        O—C(═O)—N(H)(C₁₋₆-alkyl), O—C(═O)—N(C₁₋₆-alkyl)₂;        or represents        C₃₋₆-cycloalkyl, which is unsubstituted or substituted with 1,        2, 3, 4, or 5 substituents independently from one another        selected from the group consisting of F, Cl, CF₃, ═O, OCF₃, OH,        O—C₁₋₆-alkyl, C₁₋₈-alkylen-OH and C₁₋₆-alkyl; or        3 to 7 membered heterocyclyl, which contains 1 or 2 heteroatoms        or heteroatom groups independently from one another selected        from the group consisting of O, S, S(═O), S(═O)₂, NH and        N—C₁₋₆-alkyl, and which is unsubstituted or substituted with 1,        2, 3, 4 or 5 substituents independently from one another        selected from the group consisting of F, Cl, CF₃, OCF₃, CN,        C₁₋₆-alkyl and O—C₁₋₆-alkyl; or        heteroaryl, which contains at least one nitrogen atom and which        is unsubstituted or substituted with 1, 2 or 3 substituents        independently from one another selected from the group        consisting of F, Cl, CN, CF₃, OCF₃, C₁₋₈-alkylen-OH, C₁₋₆-alkyl,        OH, O—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, NH₂,        NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, O—C(═O)—NH₂, C(═O)—NH₂,        C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂,        C(═O)—O—C₁₋₆-alkyl.

Preferred heteroaryl residues, which contain at least one nitrogen atom,are selected from pyridine, pyrimidine, pyrazine, pyridazine, triazine,quinoline, isoquinoline, phthalazine, naphtheridine, quinoxaline,quinazoline, indole, isoindole, pyrrole, imidazole, pyrazole,1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole,isothiazole, oxadiazole and thiadiazole.

More preferably, R¹⁰ represents a part structure of general formulaSF-III,

wherein R¹³ is selected from the group consisting ofH, F, Cl, CN, CF₃, OCF₃, O—C₁₋₆-alkylen-OH, C₁₋₈-alkylen-OH, C₁₋₆-alkyl,OH, O—C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂,S(═O)₂—N(H)C₁₋₆-alkyl, S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, N(H)—C(═O)—NH₂,N(H)—C(═O)—N(H)(C₁₋₆-alkyl), N(H)—C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl;N(H)—C(═O)—C₁₋₆-alkyl and N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl.

Still more preferably, R¹⁰ represents a part structure of generalformula SF-III, wherein R¹³ is selected from the group consisting of H,OH, F, Cl, CN, S(═O)₂—C₁₋₆-alkyl, NH₂, N(H)—C(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, O—C₁₋₆-alkyl, C(═O)—NH₂, C(═O)—N(H)(C₁₋₆-alkyl)and C(═O)—O—C₁₋₆-alkyl.

In a preferred embodiment of the invention, the general formula SF-IIIis selected from formulae SF-IIIa to SF-IIIo

whereinx represents 0, 1 or 2; y represents 0 or 1; z represents 0, 1 or 2; onthe condition that the sum of x, y and z is 1, 2, 3, 4, 5 or 6.

Preferred are compounds according formula (I), that are characterizedthat R¹⁰ is represented by any part structure the general formulaeSF-IIIa to SF-IIIo, wherein x represents 1, y represents 0 and zrepresents 0.

Also preferred are compounds according formula (I), that arecharacterized that R¹⁰ is represented by any part structure the generalformulae SF-IIIa to SF-IIIo, wherein x represents 1, y represents 1 andz represents 0.

Also preferred are compounds according formula (I), that arecharacterized that R¹⁰ is represented by any part structure the generalformulae SF-IIIa to SF-IIIo, wherein x represents 0, y represents 1 andz represents 0.

Also preferred are compounds according formula (I), that arecharacterized that R¹⁰ is represented by any part structure the generalformulae SF-IIIa to SF-IIIo, wherein x represents 0, y represents 1 andz represents 1.

In a particularly preferred embodiment of the first aspect of theinvention, the compound according to general formula (I) ischaracterized in that R¹⁰ is selected from the group consisting of

methyl, ethyl, 2-propyl (iso-propyl), 1-propyl (n-propyl), 1-butyl,2-butyl, 2-methyl-propyl, 1,1-dimethyl-ethyl (tert-butyl), 1-pentyl,2-pentyl, 3-pentyl, 2-methyl-butyl, 2,2-dimethyl-propyl (neo-pentyl),1-hexyl, 2-hexyl, 3-hexyl, 3,3-dimethyl-butyl, cyclopropyl,cyclopropylmethyl, 2-cyclopropyl-ethyl, 1-cyclopropyl-ethyl as well as

wherein

R¹⁶ represents 1, 2 or 3 substituents, selected from C₁₋₆-alkyl, CF₃, F,Cl, CN, OH, OCF₃, O—C₁₋₆-alkyl, NH₂, N(H)C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂,1-pyrrolidinyl, 1-piperidinyl, 4-methyl-piperidin-1-yl or 1-morpholinyl,

and R¹⁷ represents H or C₁₋₆-alkyl.

In a particularly preferred embodiment, R⁹ represents H or C₁₋₆-alkyland

R¹⁰ representsC₃₋₆-cycloalkyl, which is unsubstituted or substituted with 1, 2, 3, 4or 5 substituents independently from one another selected from the groupconsisting of F, Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₈-alkylen-OHand C₁₋₆-alkyl; or3 to 7 membered heterocyclyl, which contains 1 or 2 heteroatoms orheteroatom groups independently from one another selected from the groupconsisting of O, S, S(═O), S(═O)₂, NH and N—C₁₋₆-alkyl, and which isunsubstituted or substituted with 1, 2, 3, 4 or 5 substituentsindependently from one another selected from the group consisting of F,Cl, CF₃, OCF₃, ON, C₁₋₆-alkyl, C₁₋₈-alkylen-OH and O—C₁₋₆-alkyl; orheteroaryl, which contains at least one nitrogen atom and which isunsubstituted or substituted with 1, 2 or 3 substituents independentlyfrom one another selected from the group consisting of F, Cl, CN, CF₃,OCF₃, C₁₋₈-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,S(═O)₂—NH₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, O—C(═O)—NH₂, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; ora part structure of general formula SF-III

whereinx represents 0, 1 or 2; y represents 0, 1 or 2; z represents 0, 1 or 2;on the condition that the sum of x, y and z is 1, 2, 3, 4, 5 or 6;R¹¹ and R¹² are independently from one another selected from H orC₁₋₆-alkyl; orR¹¹ and R¹² together with the carbon atom connecting them form aC₃₋₆-cycloalkyl or a 3 to 7 membered heterocyclyl, which contains 1 or 2heteroatoms or heteroatom groups independently from one another selectedfrom the group consisting of O, S, S(═O), S(═O)₂, NH and N—C₁₋₆-alkyl,wherein said C₃₋₆-cycloalkyl or 3 to 7 membered heterocyclyl may beunsubstituted or substituted with 1, 2, 3, 4 or 5 substituentsindependently from one another selected from the group consisting of F,Cl, CF₃, OCF₃, CN, C₁₋₆-alkyl and O—C₁₋₆-alkyl;R¹³ is selected from the group consisting ofH, F, Cl, CN, CF₃, OCF₃, C₁₋₈-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl,S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl,S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, N(H)—C(═O)—NH₂,N(H)—C(═O)—N(H)(C₁₋₆-alkyl), N(H)—C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl;N(H)—C(═O)—C₁₋₆-alkyl and N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl,or representsC₃₋₆-cycloalkyl, which is unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents independently from one another selected from the groupconsisting of F, Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₈-alkylen-OHand C₁₋₆-alkyl; or3 to 7 membered heterocyclyl, which contains 1 or 2 heteroatoms orheteroatom groups independently from one another selected from the groupconsisting of O, S, S(═O), S(═O)₂, NH and N—C₁₋₆-alkyl, and which isunsubstituted or substituted with 1, 2, 3, 4 or 5 substituentsindependently from one another selected from the group consisting of F,Cl, CF₃, OCF₃, CN, C₁₋₆-alkyl and O—C₁₋₆-alkyl; or heteroaryl, whichcontains at least one nitrogen atom and which is unsubstituted orsubstituted with 1, 2 or 3 substituents independently from one anotherselected from the group consisting of F, Cl, CN, CF₃, OCF₃,C₁₋₈-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,S(═O)₂—NH₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, O—C(═O)—NH₂, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl.

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that R⁹ and R¹⁰together with the nitrogen atom connecting them form a 3 to 7 memberedheterocyclyl, unsubstituted or substituted with 1, 2, 3, 4 or 5substituents selected from the group consisting of F, Cl, CN, CF₃, ═O,OH, C₁₋₆-alkyl, O—C₁₋₆-alkyl, C₁₋₆-alkylen-OH, OCF₃, SO₂(C₁₋₆-alkyl),SO₂NH₂, SO₂N(H)C₁₋₆-alkyl, SO₂N(C₁₋₆-alkyl)₂,C₁₋₆-alkylen-SO₂(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,(C═O)C₁₋₆-alkyl, C₃₋₆-cycloalkyl or 3 to 7 membered heterocyclyl, ineach case unsubstituted or mono- or polysubstituted.

Preferably, R⁹ and R¹⁰ together with the nitrogen atom connecting themform a heterocyclyl selected from the group consisting of

whereinR¹⁴ denotes 0, 1, 2, 3 or 4 substituents which are in each caseindependently of each other selected from the group consisting of F, Cl,CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₈-alkylen-OH, SO₂(C₁₋₆-alkyl),C₁₋₈-alkylen-SO₂(C₁₋₆-alkyl), and C₁₋₆-alkyl; orR¹⁴ denotes at least two substituents, wherein two substituents R¹⁴stand together for a C₁₋₈-alkylen-group, substituted or unsubstituted,wherein optionally one or more C-atoms of the C₁₋₈-alkylen-group isreplaced by a heteroatom or heteroatom group, selected of O, N—R¹⁵, S,S(O) and S(O)₂, and wherein these two substituents R¹⁴ are positioned atdifferent carbon atoms of the heterocyclyl residue, so theC₁₋₈-alkylen-group represents a bridge to form a bicyclic heterocyclylresidue; orR¹⁴ denotes at least two substituents, wherein two substituents R¹⁴stand together for a C₂₋₆-alkylen-group, substituted or unsubstituted,wherein optionally one or more C-atoms of the C₂₋₆-alkylen-group isreplaced by a heteroatom or heteroatom group, selected from O, N—R¹⁵, S,S(O) and S(O)₂, and wherein these two substituents R¹⁴ are positioned atthe same carbon atom of the heterocyclyl residue, so theC₂₋₆-alkylen-group forms a spiro-heterocyclyl residue;andR¹⁵ represents H, C₁₋₆-alkyl or (C═O)C₁₋₆-alkyl.

More preferably,

R⁹ and R¹⁰ together with the nitrogen atom connecting them form aheterocycloaliphatic residue selected from the group consisting of

whereinR¹⁴ denotes 0, 1, 2, 3 or 4 substituents which are in each caseindependently of each other selected from the group consisting of F, Cl,CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₆-alkylen-OH,C₁₋₆-alkylen-SO₂(C₁₋₆-alkyl), SO₂(C₁₋₆-alkyl) and C₁₋₆-alkyl;orR¹⁴ denotes at least two substituents, wherein two substituents R¹⁴stand together for a C₁₋₆-alkylen-group, substituted or unsubstituted,wherein optionally one or more C-atoms of the C₁₋₆-alkylen-group isreplaced by a heteroatom or heteroatom group, selected of O, N—R¹⁵, S,S(O) and S(O)₂, and wherein these two substituents R¹⁴ are positioned atdifferent carbon atoms of the heterocyclyl, so the C₁₋₆-alkylen-grouprepresents a bridge to form a bicyclic heterocyclyl;orR¹⁴ denotes at least two substituents, wherein two substituents R¹⁴stand together for a C₂₋₆-alkylen-group, substituted or unsubstituted,wherein optionally one or more C-atoms of the C₂₋₆-alkylen-group isreplaced by a heteroatom or heteroatom group, selected of O, N—R¹⁵, S,S(O) and S(O)₂, and wherein these two substituents R¹⁴ are positioned atthe same carbon atom of the heterocyclyl, so the C₂₋₆-alkylen-groupforms a spiro-heterocyclyl; andR¹⁵ represents H, C₁₋₆-alkyl or (C═O)C₁₋₆-alkyl.

Most preferred,

R⁹ and R¹⁰ together with the nitrogen atom connecting them form aheterocycloaliphatic residue selected from the group consisting of

In another embodiment of the first aspect of the invention, the compoundaccording to general formula (I) is characterized in that

the compound of general formula (I) is a compound according to generalformula (Ia) or (Ib),

whereinHet is select from group consisting of pyrrol, thienyl, pyrazolyl,imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl,pyrimidinyl and pyridazinyl, each substituted by zero or one or twosubstituents of the group consisting of R⁶ and R⁷,wherein R⁶ and R⁷ are each independently of one another selected fromthe group consisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH;OCF₃; OCF₂H; OCFH₂; O—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl;cyclopropyl or O-cyclopropyl;R⁹ represents H or C₁₋₆-alkyl; andR¹⁰ representsC₃₋₆-cycloalkyl, which is unsubstituted or substituted with 1, 2 or 3substituents independently from one another selected from the groupconsisting of F, Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₆-alkylen-OHand C₁₋₆-alkyl;orrepresents a part structure of general formula SF-III

whereinx represents 0, 1 or 2; y represents 0, 1 or 2; z represents 0, 1 or 2;on the condition that the sum of x, y and z is 1, 2, 3, 4, 5 or 6;R¹¹ and R¹² are independently from one another selected from H orC₁₋₆-alkyl;R¹³ is selected from the group consisting ofH, F, Cl, CN, OH, O—C₁₋₆-alkyl, O—(C═O)C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl,S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl,S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,N(H)—C(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl,N(H)—C(═O)—NH₂, N(H)—C(═O)—N(H)(C₁₋₆-alkyl), N(H)—C(═O)—N(C₁₋₆-alkyl)₂;orR⁹ and R¹⁰ together with the nitrogen atom connecting them form aheterocyclyl, selected from the group consisting of

whereinR¹⁴ denotes 0, 1 or 2 substituents which are in each case independentlyof each other selected from the group consisting of F, Cl, CF₃, ═O,OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₆-alkylen-OH, C₁₋₆-alkylen-SO₂(C₁₋₆-alkyl),SO₂(C₁₋₆-alkyl) and C₁₋₆-alkyl;andR¹⁵ represents H, C₁₋₆-alkyl or (C═O)C₁₋₆-alkyl.

In another preferred embodiment of the first aspect of the invention,the compound according to general formula (I) is characterized in that

the compound of general formula (I) is a compound according to generalformula (Ia) or (Ib),whereinHet is select from group consisting of pyrrol, thienyl, pyrazolyl,imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl,pyrimidinyl and pyridazinyl, each substituted by zero or one or twosubstituents of the group consisting of R⁶ and R⁷,wherein R⁶ and R⁷ are each independently of one another selected fromthe group consisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH;OCF₃; OCF₂H; OCFH₂; O—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl;cyclopropyl or O-cyclopropyl;R⁹ represents H or methyl; andR¹⁰ representsethyl, 2-propyl (iso-propyl), 1-propyl (n-propyl), 1-butyl, 2-butyl,2-methyl-propyl, 1,1-dimethyl-ethyl (tert-butyl), 1-pentyl, 2-pentyl,3-pentyl, 2-methyl-butyl, 2,2-dimethyl-propyl (neo-pentyl), 1-hexyl,2-hexyl, 3-hexyl, 3,3-dimethyl-butyl, cyclopropyl, cyclopropylmethyl,2-cyclopropyl-ethyl, 1-cyclopropyl-ethyl as well as

orR⁹ and R¹⁰ together with the nitrogen atom connecting them form aheterocyclyl, selected from the group consisting of

In another preferred embodiment of the first aspect of the invention,the compound according to general formula (I) is characterized in that

the compound of general formula (I) is a compound according to generalformula (Ia) or (Ib),wherein Het is select from group consisting ofpyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl,thiophen-2-yl, thiophen-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazol-4-yl,oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, each substitutedby zero or one or two substituents of the group consisting of R⁶ and R⁷,wherein R⁶ and R⁷ are each independently of one another selected fromthe group consisting of F; Cl; CN; CF₃; CH₃; OH; OCF₃ and OCH₃.R⁹ represents H or methyl; andR¹⁰ representsethyl, 2-propyl (iso-propyl), 1-propyl (n-propyl), 1-butyl, 2-butyl,2-methyl-propyl, 1,1-dimethyl-ethyl (tert-butyl), 1-pentyl, 2-pentyl,3-pentyl, 2-methyl-butyl, 2,2-dimethyl-propyl (neo-pentyl), 1-hexyl,2-hexyl, 3-hexyl, 3,3-dimethyl-butyl, cyclopropyl, cyclopropylmethyl,2-cyclopropyl-ethyl, 1-cyclopropyl-ethyl as well as

orR⁹ and R¹⁰ together with the nitrogen atom connecting them form aheterocyclyl, selected from the group consisting of

Particularly preferred compounds according to the invention are selectedfrom the group consisting of

-   01    1-Benzyl-N-(2,2-dimethyl-propyl)-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   02    [1-Benzyl-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   03    1-Benzyl-3-(3,5-dimethyl-isoxazol-4-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   04    [1-Benzyl-3-(3,5-dimethyl-isoxazol-4-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   05    1-Benzyl-3-(6-cyano-4-methyl-pyridin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   06    5-[1-Benzyl-4-methyl-2-(morpholine-4-carbonyl)-5-(trifluoromethyl)-1H-pyrrol-3-yl]-4-methyl-pyridine-2-carbonitrile-   07    1-Benzyl-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   08    [1-Benzyl-3-(6-chloro-4-methyl-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   09    1-Benzyl-N-(2,2-dimethyl-propyl)-3-(6-methoxy-4-methyl-pyridin-3-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   10    [1-Benzyl-3-(6-methoxy-4-methyl-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   11    1-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyrazin-2-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   12    [1-Benzyl-4-methyl-3-pyrazin-2-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   13    1-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyridazin-4-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   14    [1-Benzyl-4-methyl-3-pyridazin-4-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   15    1-Benzyl-N-(2,2-dimethyl-propyl)-3-(5-fluoro-pyridin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   16    [1-Benzyl-3-(5-fluoro-pyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   17    1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   18    [1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   19    1-Benzyl-N-(2,2-dimethyl-propyl)-3-(5-fluoro-pyrimidin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   20    [1-Benzyl-3-(5-fluoro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   21    1-Benzyl-N-(2,2-dimethyl-propyl)-3-(5-methoxy-pyrimidin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   22    1-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyrimidin-2-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   23    [1-Benzyl-4-methyl-3-pyrimidin-2-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   24    1-Benzyl-3-(6-chloro-pyridazin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   25    [1-Benzyl-3-(6-chloro-pyridazin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   26    [1-Benzyl-4-methyl-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   27    [1-Benzyl-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   28 1-Benzyl-3-(5-chloro-pyridin-2-yl)-N-(2,2-di    methyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   29    1-Benzyl-3-(5-chloro-pyridin-2-yl)-N,4-dimethyl-N-(2-methylsulfonyl-ethyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   30    [1-Benzyl-3-(5-chloro-pyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   31    1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-(2-cyano-2-methyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   32    1-Benzyl-N-(2-carbamoyl-2-methyl-propyl)-3-(5-chloro-pyrimidin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   33    4-[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carbonyl]-piperazin-2-one-   34    [1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone-   35    [1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-(1,1-dioxo-[1,4]thiazinan-4-yl)-methanone-   36    1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-cyclopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   37    1-Benzyl-N-(2,2-dimethyl-propyl)-3-(2-methoxy-pyrimidin-5-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   38    [1-Benzyl-3-(2-methoxy-pyrimidin-5-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   39    1-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyrimidin-5-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   40    [1-Benzyl-4-methyl-3-pyrimidin-5-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   41    1-Benzyl-3-(5-chloro-thiophen-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   42    1-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   43    1-Benzyl-N-(2,2-dimethyl-propyl)-3-(6-hydroxy-pyridin-3-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   44    [1-Benzyl-3-(6-hydroxy-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   45    1-Benzyl-N-(2,2-dimethyl-propyl)-3-(6-methoxy-pyridin-3-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   46    [1-Benzyl-3-(6-methoxy-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   47    1-Benzyl-N-(2,2-dimethyl-propyl)-3-(5-methoxy-pyrazin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   48    [1-Benzyl-3-(5-methoxy-pyrazin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone-   49    1-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   50    1-Benzyl-3-(5-chloro-pyridin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   51    1-Benzyl-N-isopropyl-N,4-dimethyl-3-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   52    1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-isopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   53    1-Benzyl-3-(5-chloro-pyridin-2-yl)-N-isopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   54    1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   55    1-Benzyl-3-(5-cyclopropyl-pyrazin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   56    1-Benzyl-3-(5-cyclopropyl-pyrimidin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   57    1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N,4-dimethyl-N-[2-methyl-2-(methylcarbamoyl)-propyl]-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   58    1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-[2-(dimethyl-carbamoyl)-2-methyl-propyl]-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   59    1-Benzyl-N-isopropyl-N,4-dimethyl-3-(1-methyl-1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide-   60    1-Benzyl-N-isopropyl-N,4-dimethyl-3-[5-(methylsulfinyl)-pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide-   61    1-Benzyl-3-[5-chloro-3-(methylsulfinyl)-pyridin-2-yl]-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic    acid amide    optionally in the form of a single stereoisomer or a mixture of    stereoisomers, in the form of the free compound and/or a    physiologically acceptable salt or solvate thereof.

Furthermore, preference may be given to compounds according to theinvention that cause at least a 50% inhibition, which is present at aconcentration of 3 μM, in a fluorescent assay for CaV2.2 channels withHEK293 cells in which human CaV2.2 channels were stably expressed at aconcentration of less 3 μM, preferably less than 1000 nM, particularlypreferably less than 300 nM, most particularly preferably less than 100nM, even more preferably less than 75 nM, additionally preferably lessthan 50 nM, most preferably less than 10 nM.

In the process, the Ca²⁺ influx is quantified in the FLIPR assay withthe aid of a Ca²⁺-sensitive dye (type Fluo-4, Molecular Probes EuropeBV, Leiden, the Netherlands) in a fluorescent imaging plate reader(FLIPR 3, Molecular Devices, Sunnyvale, USA), as described hereinafter.

The compounds according to the invention and corresponding stereoisomersand also the respective corresponding acids, bases, salts and solvatesare suitable for the treatment and/or prophylaxis of one or moredisorders and/or diseases selected from the group consisting of pain,preferably pain selected from the group consisting of acute pain,chronic pain, visceral pain, headache pain, inflammatory pain and mixedpain; stroke (the neuronal damage resulting from head trauma); mooddisorders; epilepsy; schizophrenia, and neurodegenerative disorders.

The present invention further relates to a compound according to thepresent invention for CaV2.2 calcium channel regulation, preferably foruse in CaV2.2 calcium channel blockage.

The present invention therefore further relates to a compound accordingto the present invention for the prophylaxis and/or treatment ofdisorders and/or diseases which are mediated, at least in part, at leastin part, by CaV2.2 channels.

The term “disorders and/or diseases which are mediated, at least inpart, by CaV2.2 channels”, is intended to include each of or all of thedisease states.

The substances according to the invention hence act, for example, onCaV2.2 channels relevant in connection with various diseases, so thatthey are suitable as a pharmacologically active compound inpharamceutical compositions.

The compounds according to the first aspect of the present invention andthe corresponding stereoisomers and the respective salts and solvatesare toxicologically safe and are therefore suitable as pharmacologicallyactive ingredients in pharmaceutical compositions.

In another sepcet of the present invention, the invention therefore alsoprovides pharmaceutical compositions, containing at least one compoundaccording to the invention and optionally one or more suitable,pharmaceutically compatible auxiliaries and/or, if appropriate, one ormore further pharmacologically active compounds.

The pharmaceutical composition according to the invention is suitablefor administration to adults and children, including toddlers andbabies.

The pharmaceutical composition according to the invention may be foundas a liquid, semisolid or solid pharmaceutical form, for example in theform of injection solutions, drops, juices, syrups, sprays, suspensions,tablets, patches, capsules, plasters, suppositories, ointments, creams,lotions, gels, emulsions, aerosols or in multiparticulate form, forexample in the form of pellets or granules, if appropriate pressed intotablets, decanted in capsules or suspended in a liquid, and also beadministered as much.

In addition to at least one compound according to the invention, ifappropriate in the form of one of its pure stereoisomers, in particularenantiomers or diastereomers, its racemate or in the form of mixtures ofthe stereoisomers, in particular the enantiomers or diastereomers, inany desired mixing ratio, or if appropriate in the form of acorresponding salt or respectively in the form of a correspondingsolvate, the pharmaceutical composition according to the inventionconventionally contains further physiologically compatiblepharmaceutical auxiliaries which can for example be selected from thegroup consisting of excipients, fillers, solvents, diluents,surface-active substances, dyes, preservatives, blasting agents, slipadditives, lubricants, aromas and binders.

The selection of the physiologically compatible auxiliaries and also theamounts thereof to be used depend on whether the pharmaceuticalcomposition is to be applied orally, subcutaneously, parenterally,intravenously, intraperitoneally, intradermally, intramuscularly,intranasally, buccally, rectally or locally, for example to infectionsof the skin, the mucous membranes and of the eyes. Preparations in theform of tablets, dragées, capsules, granules, pellets, drops, juices andsyrups are preferably suitable for oral application; solutions,suspensions, easily reconstitutable dry preparations and also sprays arepreferably suitable for parenteral, topical and inhalative application.The compounds according to the invention used in the pharmaceuticalcomposition according to the invention in a repository in dissolved formor in a plaster, agents promoting skin penetration being added ifappropriate, are suitable percutaneous application preparations. Orallyor percutaneously applicable preparation forms can release therespective compound according to the invention also in a delayed manner.

The pharmaceutical compositions according to the invention are preparedwith the aid of conventional means, devices, methods and process knownin the art, such as are described for example in “Remington'sPharmaceutical Sciences”, A. R. Gennaro (Editor), 17^(th) edition, MackPublishing Company, Easton, Pa., 1985, in particular in Part 8, Chapters76 to 93. The corresponding description is introduced herewith by way ofreference and forms part of the disclosure. The amount to beadministered to the patient of the respective compounds according to theinvention of the above-indicated general formula I may vary and is forexample dependent on the patient's weight or age and also on the type ofapplication, the indication and the severity of the disorder.Conventionally 0.001 to 100 mg/kg, preferably 0.05 to 75 mg/kg,particularly preferably 0.05 to 50 mg of at least one such compoundaccording to the invention are applied per kg of the patient's bodyweight.

CaV2.2 channels are believed to be involved in a variety of diseases ordisorders in mammals such as humans. These include pain (e.g.; acutepain, chronic pain, visceral pain, headache pain, inflammatory pain,mixed pain), stroke (the neuronal damage resulting from head trauma),epilepsy, mood disorders, schizophrenia, neurodegenerative disorders.

Another embodiment of the present invention is at least one compoundaccording the present invention for the treatment and/or prophylaxis ofone or more disorders selected from the group consisting of pain,preferably pain selected from the group consisting of acute pain,chronic pain, visceral pain, headache pain, inflammatory pain and mixedpain; stroke (the neuronal damage resulting from head trauma); mooddisorders; epilepsy; schizophrenia, and neurodegenerative disorders.

Another embodiment of the present invention is at least one compoundaccording to the present invention for the treatment and/or prophylaxisof pain, in particular acute pain and/or chronic pain and/or visceralpain and/or headache pain and/or inflammatory pain and/or mixed pain.

Acute pain according to the invention might include nociceptive pain andpost-operative or surgical pain. Chronic pain according to the inventionmight include peripheral neuropathic pain such as post-herpeticneuralgia, traumatic nerve injury, nerve compression or entrapment,small fibre neuropathy, diabetic neuropathy, neuropathic cancer pain,failed back surgery Syndrome, trigeminal neuralgia, phantom limb pain;neuroma pain, complex regional pain syndrome, chronic arthritic pain andrelated neuralgias, and pain associated with cancer, chemotherapy, HIVand HIV treatment-induced neuropathy; central neuropathic pain such asmultiple sclerosis related pain, Parkinson disease related pain,post-stroke pain, post-traumatic spinal cord injury pain, and pain indementia; musculoskeletal pain such as osteoarthritic pain andfibromyalgia syndrome. In treating osteoarthritic pain, joint mobilitywill also improve as the underlying chronic pain is reduced. Thus, atleast one compound for treatment of osteoarthritic pain inherently willalso improve joint mobility in patients suffering from osteoarthritis.Visceral pain according to the invention might include interstitialcystitis, irritable bowel syndrome, Crohn's disease and chronic pelvicpain syndrome. Inflammatory pain according to the invention mightinclude rheumatoid arthritis and endometriosis. Headachepain accordingto the invention might include migraine, cluster headache, tensionheadache syndrome, facial pain and headache caused by other diseases.Mixed pain according to the invention might include lower back pain,neck and shoulder pain, burning mouth syndrome and complex regional painsyndrome.

In another embodiment of the invention, at least one compound accordingto the present invention is particularly suitable for the treatmentand/or prophylaxis of mood disorders.

Mood disorders according to the invention might include anxietydisorder, social anxiety disorder, panic disorder, specific phobias, forexample, specific animal phobias, social phobias, obsessive-compulsivedisorder, agoraphobia, post-traumatic stress syndrome, addiction(including dependence, withdrawal and/or relapse of medication,including opioids, but also drugs such as cocaine, opioids, alcohol andnicotine), generalised anxiety disorders, single episodic or recurrentmajor depressive disorders and dysthymic disorders, or bipolardisorders, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder.

In another embodiment of the invention, at least one compound accordingto the present invention is particularly suitable for the treatmentand/or prophylaxis of epilepsy.

Epilepsy according to the invention might include partial seizures suchas temporal lobe epilepsy, absence seizures generalized seizures, andtonic/clonic seizures.

In yet another embodiment of the invention, at least one compoundaccording to the present invention is particularly suitable for thetreatment and/or prophylaxis of neurodegenerative disorders.

Neurodegenerative disorders according to the invention might includeParkinson's disease, Alzheimer's disease, multiple sclerosis,neuropathies, Huntington's disease, presbycusis and amyotrophic lateralsclerosis (ALS).

Particularly preferably, at least one compound according to the presentinvention is suitable for the treatment and/or prophylaxis of one ormore disorders and/or diseases selected from the group consisting ofpain, preferably of pain selected from the group consisting of acutepain, chronic pain, visceral pain, headache pain, inflammatory pain andmixed pain; migraine; depression; neurodegenerative diseases, preferablyselected from the group consisting of multiple sclerosis, Alzheimer'sdisease, Parkinson's disease and Huntington's disease; cognitivedysfunctions, preferably cognitive deficiency states, particularlypreferably memory disorders; medication dependency; misuse ofmedication; withdrawal symptoms in medication dependency; development oftolerance to medication, preferably development of tolerance to naturalor synthetic opioids; drug dependency; misuse of drugs; withdrawalsymptoms in drug dependency; alcohol dependency; misuse of alcohol andwithdrawal symptoms in alcohol dependency.

Most particularly preferably, at least one compound according to thepresent invention according to the invention is suitable for thetreatment and/or prophylaxis of pain, preferably of pain selected fromthe group consisting of acute pain, chronic pain, visceral pain,headache pain, inflammatory pain and mixed pain.

The present invention further relates to a compound according to thepresent invention and one or more additional pharmaceutically activeagents for use in the prophylaxis and/or treatment of disorders and/ordiseases which are mediated, at least in part, at least in part, byCaV2.2 channels.

In particular, the present invention therefore further relates to acompound according to the present invention and one or more additionalpharmaceutically active agents for the prophylaxis and/or treatment ofdisorders and/or diseases selected from the group consisting of pain,preferably pain selected from the group consisting of acute pain,chronic pain, visceral pain, headache pain, inflammatory pain and mixedpain; stroke (the neuronal damage resulting from head trauma); mooddisorders; epilepsy; schizophrenia, and neurodegenerative disorders.

Most particularly preferred is a compound according to the presentinvention one or more additional pharmaceutically active agents for theprophylaxis and/or treatment of pain, preferably of pain selected fromthe group consisting of acute pain, chronic pain, visceral pain,headache pain, inflammatory pain and mixed pain.

Additional pharmaceutically active agents in the treatment of pain mayinclude, for example, i) opiate agonists or antagonists, ii) calciumchannel antagonists, iii) 5HT receptor agonists or antagonists, iv)sodium channel antagonists, v) NMDA receptor agonists or antagonists,vi) COX-2 selective inhibitors, vii) NKI antagonists, viii)non-steroidal anti-inflammatory drugs (“NSAID”), ix) selective serotoninreuptake inhibitors (“SSRI”) and/or selective serotonin andnorepinephrine reuptake inhibitors (“SSNRI”), x) tricyclicantidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii)valproate, xiv) neurontin (gabapentin), xv) pregabalin.

Additional pharmaceutically active agents in the treatment of depressionor anxiety can include other anti-depressant or anti-anxiety agents,such as norepinephrine reuptake inhibitors, selective serotonin reuptakeinhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversibleinhibitors of monoamine oxidase (RIMAs), serotonin and noradrenalinereuptake inhibitors (SNRIs), adrenoreceptor antagonists, atypicalanti-depressants, benzodiazepines, 5-HT1 A agonists or antagonists,especially 5-HT1 A partial agonists, neurokinin 1 receptor antagonists,corticotropin releasing factor (CRF) antagonists, and pharmaceuticallyacceptable salts thereof.

Another embodiment of the present invention therefore relates to use ofat least one compound according to the present invention for thepreparation of a pharmaceutical composition for the treatment and/orprophylaxis of one or more disorders or diseases, particularly selectedfrom the group consisting of pain, preferably pain selected from thegroup consisting of acute pain, chronic pain, visceral pain, headachepain, inflammatory pain and mixed pain; stroke; mood disorders;epilepsy; schizophrenia, and neurodegenerative disorders.

Another aspect of the present invention is a method of treatment and/orprophylaxis of disorders and/or diseases in a mammal, preferably ofdisorders and/or diseases selected from the group consisting of pain,preferably pain selected from the group consisting of acute pain,chronic pain, visceral pain, headache pain, inflammatory pain and mixedpain; stroke; mood disorders; epilepsy; schizophrenia, andneurodegenerative disorders, which comprises administering an effectiveamount of at least one compound according to the present invention tothe mammal.

Another embodiment of the present invention is a method for CaV2.2calcium channel regulation, preferably for use in CaV2.2 calcium channelblockage, and, further, a method of treatment and/or prophylaxis ofdisorders and/or diseases, which are mediated, at least in part, byCaV2.2 channels, in a mammal, preferably of disorders and/or diseasesselected from the group consisting of pain, preferably pain selectedfrom the group consisting of acute pain, chronic pain, visceral pain,headache pain, inflammatory pain and mixed pain; stroke; mood disorders;epilepsy; schizophrenia, and neurodegenerative disorders, whichcomprises administering an effective amount of at least one compoundaccording to the present invention to the mammal.

All preferred embodiments of the first aspect of the invention arepreferred vice versa for the other aspects and embodiments.

The effectiveness against pain can be shown, for example, in the Bennettor Chung model (Bennett, G. J. and Xie, Y. K., A peripheralmononeuropathy in rat that produces disorders of pain sensation likethose seen in man, Pain 1988, 33(1), 87-107; Kim, S. H. and Chung, J.M., An experimental model for peripheral neuropathy produced bysegmental spinal nerve ligation in the rat, Pain 1992, 50(3), 355-363),by tail flick experiments (e.g. according to D'Amour und Smith (J.Pharm. Exp. Ther. 72, 74 79 (1941)) or by the formalin test (e.g.according to D. Dubuisson et al., Pain 1977, 4, 161-174).

Examples

The compounds according to the invention can be prepared in the mannerdescribed below. The following examples further illustrate the inventionbut are not to be construed as limiting its scope.

All starting materials which are not explicitly described were eithercommercially available (the details of suppliers such as for exampleAcros, Avocado, Aldrich, Apollo, Bachem, Fluka, FluoroChem, Lancaster,Manchester Organics, MatrixScientific, Maybridge, Merck, Rovathin,Sigma, TCI, Oakwood, etc. can be found in the Symyx® Available ChemicalsDatabase of MDL, San Ramon, US or the SciFinder® Database of the ACS,Washington D.C., US, respectively, for example) or the synthesis thereofhas already been described precisely in the specialist literature(experimental guidelines can be found in the Reaxys® Database ofElsevier, Amsterdam, NL or the SciFinder® Database of the ACS,Washington D.C., US, respectively, for example) or can be prepared usingthe conventional methods known to the person skilled in the art.

The stationary phase used for the column chromatography was silica gel60 (0.04-0.063 mm) from E. Merck, Darmstadt. The reactions were, ifnecessary, carried out under an inert amosphere (mostly nitrogen).

The yields of the compounds prepared are not optimized. The mixingratios of solvents are usually stated in the volume/volume ratio. Thereactions were, if necessary, carried out under an inert amosphere(mostly N₂). The number of equivalents of reagents and the amounts ofsolvents employed as well as the reaction temperatures and times canvary slightly between different reactions carried out by the same(general) method. The work-up and purification methods were adaptedaccording to the characteristic properties of each compound and can varyslightly for analogous/general methods.

All the intermediate products and exemplary compounds were analyticallycharacterized by means of ¹H-NMR spectroscopy. In addition, massspectrometry tests (MS, m/z for [M+H]⁺) were carried out for all theexemplary compounds and selected intermediate products.

The following abbreviations are used in the descriptions of theexperiments: MeCN=acetonitrile; NBS=N-Bromosuccinimide;EtOAc=ethylacetate; THF=tetrahydrofuran; MeOH=methanol; EtOH=ethanol;HATU=(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluoro-phosphate); DIPEA=N,N-diisopropylethylamine;n-BuLi=n-butyllithium; dppf=1,1′; bis(diphenylphosphanyl)ferrocene;HBPin=4,4,5,5-tetramethyl-1,3,2-dioxaborolane; DMF=N,N-dimethylformamid;DMSO=dimethylsulfoxid; h=hour; min=minute; tert=tertiary; RT=roomtemperature; DCM=dichloromethane; TMSCl=trimethylsilyl chloride;dba=dibenzylideneacetone; Boc=tert-butyloxycarbonyl;BOP-Cl=bis(2-oxo-3-oxazolidinyl)phosphinic chloride;CDI=carbonyldiimidazole; DME=1,2-di-methoxyethane;EDCl=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride;HOAt=1-hydroxy-7-azabenzotriazole;XPhos=2-dicyclohexyl-phosphino-2′,4′,6′-triisopropylbiphenyl; TLC=thinlayer chromatography; CC=column chromatography.

Section (A) General Synthetic Route 1:

EXAMPLES Example 011-benzyl-3-(5-methoxypyrazin-2-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide1a): Ethyl 4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

Trifluoromethanesulfonyl chloride (15.4 ml, 137.2 mmol, 1.05 eq) wasadded to the Ar degassed solution ofethyl-4-methyl-1H-pyrrole-2-carboxylate (20 g, 130.7 mmol, 1 eq), K₂HPO₄(68.2 g, 392.1 mmol, 3 eq), dichlorotris (1, 10-phenanthroline)ruthenium (II) hydrate (1.8 g, 2.6 mmol, 0.02 eq) in acetonitrile (200ml). The reaction mixture was stirred for 6 d at RT adjacent to afluorescent light bulb (23 W). The reaction mixture was diluted withEtOAc and H₂O. The aqueous layer was extracted with EtOAc (300 ml×2).Combined organic layers were dried over anhydrous Na₂SO₄, filtered,concentrated under reduced pressure to give crude product which was thenpurified by CC to yield ethyl4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (11.5 g, 40%) as awhite solid.

1b): Ethyl 3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

NBS (7.2 g, 40.7 mmol, 1 eq) was portion wise added to an ice cooledsolution of ethyl 4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate(9 g, 40.7 mmol, 1 eq) and K₂CO₃ (5.9 g, 42.7 mmol, 1.05 eq) in MeCN (90ml). The reaction mixture was stirred for 2 h at RT. The reactionmixture was diluted with EtOAc and H₂O. The aqueous layer was extractedwith EtOAc (100 ml×2). Combined organic layers were dried over anhydrousNa₂SO₄, filtered, concentrated under reduced pressure to give 12.5 g ofethyl 3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylatewhich was directly used in the next step without further purification.

1c): Ethyl1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

Benzyl bromide (6.5 ml, 55.0 mmol, 1.1 eq) was added to the solution ofethyl 3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (15g, 50.0 mmol, 1 eq) and K₂CO₃ (13.8 g, 100.0 mmol, 2 eq) in MeCN (150ml). The reaction mixture was stirred for 13 h at 80° C. Then thereaction mixture was cooled to RT and diluted with EtOAc and H₂O. Theaqueous layer was extracted with EtOAc (150 ml×2). Combined organiclayers were dried over anhydrous Na₂SO₄, concentrated under reducedpressure to give crude mass which was then purified by columnchromatography to yield ethyl1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate(18 g, 92%) as a pale yellow color oil.

1d):1-Benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid

Lithium hydroxide monohydrate (5.3 g, 128.6 mmol, 5 eq) was added to theice cold solution of ethyl1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate(10 g, 25.6 mmol, 1 eq) in THF (100 ml), MeOH (20 ml) and H₂O (50 ml).The mixture was allowed to warm up to RT and then heated up to 100° C.for 14 h, cooled to RT and then diluted with H₂O and acidified with 6NHCl (pH˜2). The aqueous layer was extracted with EtOAc (100 ml×2).Combined organic layers were dried over anhydrous Na₂SO₄, filtered,concentrated under reduced pressure to give crude mass which wastriturated with diethyl ether to afford1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid (7.7 g, 83%) as a white color solid.

1e):1-Benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

HATU (6.2 g, 16.5 mmol, 1.2 eq) and DIPEA (6.1 ml, 34.5 mmol, 2.5 eq)were added to the ice cold solution of1-benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(5 g, 13.8, 1 eq) in DMF (50 ml) and it was stirred for 10 min at sametemperature. Then 2,2-dimethylpropan-1-amine (1.4 g, 16.5 mmol, 1.2 eq)was added and the reaction mixture was warmed to RT and then stirred for15 h. The reaction mixture was diluted with EtOAc and H₂O. The aqueouslayer was extracted with EtOAc (80 ml×2). Combined organic layers weredried over anhydrous Na₂SO₄, filtered, concentrated under reducedpressure to give crude1-benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(5.1 g, 86%) as a white color solid which was directly used in next stepwithout further purification.

1f):1-Benzyl-3-bromo-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

Methyl iodide (1.4 ml, 23.2 mmol, 2 eq) was added to the ice coldsolution of1-benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(5 g, 11.6 mmol, 1 eq), NaH (0.5 g, 23.2 mmol, 2 eq) in THF (50 ml) andstirred for 2 h at RT. The reaction mass was poured onto crushed ice andextracted with EtOAc (75 ml×2). Combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure togive crude mass which was then purified by CC to afford1-benzyl-3-bromo-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(4.5 g, 87%) as a white solid.

1g):1-Benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

2.4 M n-BuLi (2.2 ml, 5.3 mmol, 1.2 eq) was added to the cooled (−78°C.) solution of1-benzyl-3-bromo-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(2 g, 4.4 mmol, 1 eq) in dry THF (40 ml) and it was stirred at sametemperature for 30 min. HBPin (3.5 ml, 22.4 mmol, 5 eq) was added to thereaction mixture and stirred for 45 min at −78° C. The reaction mass wasquenched with saturated NH₄CI solution and extracted with EtOAc (50ml×2). Combined organic layers were dried over anhydrous Na₂SO₄,filtered, concentrated under reduced pressure to yield crude mass whichwas then purified by CC to afford1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(1 g, 46%) as a white solid.

1h):1-Benzyl-3-(5-methoxypyrazin-2-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

To a solution of1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.2 g, 0.40 mmol, 1 eq.) in DMF (10 ml) was added 2M Na₂CO₃ (0.6 ml)solution and 2-bromo-5-methoxypyrazine (0.09 g, 0.48 mmol, 1.2 eq). Thesolution was degassed with argon for 5 min followed by addition ofPd(dppf)Cl₂.CH₂Cl₂ (0.02 g, 0.028 mmol, 0.07 eq.) The reaction mixtureis refluxed at 110° C. for 16 h. The reaction mass was poured ontocrushed ice, extracted with EtOAc (50 ml×2). Combined organic layerswere dried over anhydrous Na₂SO₄, filtered, concentrated under reducedpressure to yield crude mass which was then purified by CC to afford1-benzyl-3-(5-methoxypyrazin-2-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.12 g, 62%) as a white solid.

Example 021-Benzyl-3-(6-methoxypyridin-3-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

To a solution of1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.6 g, 1.21 mmol, 1 eq) in DMF (15 ml) was added 2M Na₂CO₃ (1.8 ml,3.65 mmol, 3 eq) solution and 5-bromo-2-methoxypyridine (0.19 ml, 1.46mmol, 1.2 eq). The solution was degassed with Ar for 5 min followed byaddition of Pd(dppf)Cl₂.CH₂Cl₂ (0.069 g, 0.082 mmol, 0.07 eq.) Thereaction mixture was stirred at 110° C. for 16 h. The reaction mass waspoured onto crushed ice, extracted with EtOAc (75 ml×2). Combinedorganic layer were dried over anhydrous Na₂SO₄, filtered, concentratedunder reduced pressure to yield crude mass which was then purified by CCto afford1-benzyl-3-(6-methoxypyridin-3-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.31 g, 54%) as a white solid.

Example 031-Benzyl-3-(6-hydroxypyridin-3-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

TMSCl (0.27 ml, 2.11 mmol, 4 eq) was added to a solution of1-benzyl-3-(6-methoxypyridin-3-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.25 g, 0.52 mmol, 1 eq) and KI (0.35 g, 2.11 mmol, 4 eq) in MeCN andthe reaction mixture was stirred at 80° C. for 16 h. The reactionmixture was cooled to RT, diluted with H₂O and extracted with EtOAc (75ml×2). Combined organic layers were dried over anhydrous Na₂SO₄,filtered, concentrated under reduced pressure to yield crude mass whichwas then purified by CC to afford1-benzyl-3-(6-hydroxypyridin-3-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.15 g, 62%) as a white solid.

Example 041-Benzyl-N,4-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

To a solution of1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.3 g, 0.60 mmol, 1 eq) in DMF (15 ml) was added 2M Na₂CO₃ (0.9 ml,1.82 mmol, 3 eq) solution and 4-bromo-1-methyl-1H-pyrazole (0.11 g, 0.73mmol, 1.2 eq). The solution was degassed with Ar for 5 min followed byaddition of Pd(dppf)Cl₂.CH₂Cl₂ (0.034 g, 0.042 mmol, 0.07 eq.) Thereaction mixture was stirred at 110° C. for 16 h. The reaction mass waspoured onto crushed ice and extracted with EtOAc (50 ml×2). Combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, concentratedunder reduced pressure to yield crude mass which was then purified by CCto afford1-benzyl-N,4-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.08 g, 29%) as a white solid.

Example 05(1-Benzyl-3-(5-methoxypyrazin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone5a):(1-Benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

HATU (11.34 g 29.83 mmol, 1.2 eq) and DIPEA (11.1 ml, 62.15 mmol, 2.5eq) were added to the ice cold solution of1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid (9 g, 24.86 mmol, 1 eq) in DMF (100 ml) and it was stirred for 10min at same temperature and then morpholine (2.59 g, 29.83 mmol, 1.2 eq)was added. The reaction mixture was warmed to RT and then stirred for 14h. The reaction mixture was diluted with EtOAc and H₂O. The aqueouslayer was extracted with EtOAc (300 ml×2), the combined organic layerswere washed with water (300 ml×2) and brine (300 ml×2), dried overanhydrous Na₂SO₄, filtered, concentrated under reduced pressure to yieldcrude mass which was then purified by CC to afford(1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(10.1 g, 94%) as a white color solid.

5b):(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

At −78° C. 2.4 M n-BuLi (6.74 ml, 16.17 mmol, 1.2 eq) was added to asolution of(1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(6 g, 13.4 mmol, 1 eq) in dry THF (100 ml) and the mixture was stirredat same temperature for 30 min. HBPin (10.7 ml, 67.4 mmol, 5 eq) wasadded and the reaction mixture was stirred for 45 min at −78° C. Thereaction mass was quenched with saturated NH₄CI solution and extractedwith EtOAc (300 ml×2). Combined organic layers were dried over anhydrousNa₂SO₄, concentrated under reduced pressure to yield crude mass whichwas then purified by CC to afford(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(3.2 g, 50%) as a white solid.

5c):(1-Benzyl-3-(5-methoxypyrazin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

To a solution of(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.4 g, 0.836 mmol, 1 eq) in DMF (15 ml) was added 2M Na₂CO₃ (1.2 ml,2.51 mmol, 3 eq) solution and 2-bromo-5-methoxypyrazine (0.18 mg, 1.04mmol, 1.2 eq). The solution was degassed with Ar for 5 min followed byaddition of Pd(dppf)Cl₂.CH₂Cl₂ (0.047 g, 0.058 mmol, 0.07 eq.) Thereaction mixture was stirred at 110° C. for 16 h. The reaction mass waspoured onto crushed ice and extracted with EtOAc (75 ml×2). Combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, concentratedunder reduced pressure to yield crude mass which was then purified by CCto afford(1-benzyl-3-(5-methoxypyrazin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.18 g, 47%) as a white solid.

Example 06(1-Benzyl-3-(6-methoxypyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

To a solution of(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.6 g, 1.21 mmol, 1 eq) in DMF (15 ml) was added 2M Na₂CO₃ (1.75 ml,3.51 mmol, 3 eq) solution and 5-bromo-2-methoxypyridine (0.2 ml, 1.50mmol, 1.2 eq). The solution was degassed with Ar for 5 min followed byaddition of Pd(dppf)Cl₂.CH₂Cl₂ (0.071 g, 0.047 mmol, 0.07 eq.) Thereaction mixture was stirred at 110° C. for 16 h. The reaction mass waspoured onto crushed ice and extracted with EtOAc (80 ml×2). Combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to yield crude mass which was thenpurified by CC to afford(1-benzyl-3-(6-methoxypyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)-methanone(0.3 g, 52%) as a white solid.

Example 07(1-Benzyl-3-(6-hydroxypyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

TMSCl (0.22 ml, 1.74 mmol, 4 eq) was added to a solution of(1-benzyl-3-(6-methoxypyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.20 g, 0.43 mmol, 1 eq) and KI (0.28 g, 1.74 mmol, 4 eq) in MeCN andthe reaction mixture was stirred at 80° C. for 16 h. The reaction masswas cooled to RT, diluted with H₂O and extracted with EtOAc (75 ml×2).Combined organic layers were dried over anhydrous Na₂SO₄, filtered,concentrated under reduced pressure to yield crude mass which was thenpurified by CC to afford(1-benzyl-3-(6-hydroxypyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)-(morpholino)methanone(0.08 g, 41%) as a white solid.

Example 08(1-Benzyl-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

To a solution of(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.6 g, 1.21 mmol, 1 eq) in DMF (15 ml) was added 2M Na₂CO₃ (1.75 ml,3.51 mmol, 3 eq) solution and 4-bromo-1-methyl-1H-pyrazole (0.1 ml, 1.04mmol, 1.2 eq). The solution was degassed with Ar for 5 min followed byaddition of Pd(dppf)Cl₂.CH₂Cl₂ (0.071 g, 0.047 mmol, 0.07 eq.) Thereaction mixture was stirred at 110° C. for 16 h. The reaction mass waspoured onto crushed ice and extracted with EtOAc (80 ml×2). Combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to yield crude mass which was thenpurified by CC to afford(1-benzyl-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)-methanone(0.12 g, 33%) as a white solid.

Example 091-Benzyl-N,4-dimethyl-N-neopentyl-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

To a solution of1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(1 g, 2.03 mmol, 1 eq.) in DMF (10 ml) was added 2M Na₂CO₃ (3 ml, 6.09mmol, 3 eq) solution and tert-butyl 4-bromo-1H-pyrazole-1-carboxylate(0.6 g, 2.43 mmol, 1.2 eq). The solution was degassed with Ar for 5 minfollowed by addition of bis(tri-tert-butyl phosphine) palladium (0.23 g,0.023 mmol, 0.1 eq.) The reaction mixture is refluxed at 110° C. for 16h. The reaction mass was poured onto crushed ice and extracted withEtOAc (50 ml×2). Combined organic layers were dried over anhydrousNa₂SO₄, filtered, concentrated under reduced pressure to yield crudemass which was then purified by CC to affordbenzyl-N,4-dimethyl-N-neopentyl-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.07 g, 8%) as a white solid.

Example 10(1-Benzyl-4-methyl-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

To a solution of(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(1 g, 2.09 mmol, 1 eq) in DMF (15 ml) was added 2M Na₂CO₃ (3.1 ml, 6.27mmol, 3 eq) solution and tert-butyl 4-bromo-1H-pyrazole-1-carboxylate(1.03 g, 4.18 mmol, 2 eq). The solution was degassed with Ar for 5 minfollowed by addition of bis(tri-tert-butyl phosphine) palladium (0.24 g,0.209 mmol, 0.1 eq.) The reaction mixture was stirred at 110° C. for 16h. The reaction mass was poured onto crushed ice and extracted withEtOAc (100 ml×2). Combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to yield crudemass which was then purified by CC to afford(1-benzyl-4-methyl-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)-(morpholino)methanone(0.06 g, 7%) as a white solid.

General Procedure A for Suzuki Cross-Coupling:

Under Ar, bis(tri-tert-butylphosphine)palladium(0) was added to amixture of corresponding pyrroloboronate (0.33 mmol, 1.1 eq.),heteroarylbromide (0.30 mmol, 1.0 eq) and LiOH (0.33 mmol, 1.1 eq) inDMF (1.6 mL). The mixture was heated up to 80° C. under microwaveirradiation for 1 h. The reaction mixture was allowed to RT, 2M NaOH (2ml) was added and the crude product was extracted with EtOAc (2 ml×2).Combined organic layers were concentrated under reduced pressure toyield crude mass which was then purified by flash chromatography orpreparative HPLC to afford desired compound.

Example 111-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyrimidin-5-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.31 mmol, 1.1 eq) was converted with 5-bromopyrimidine (0.28 mmol, 1.0eq) to give desired1-benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyrimidin-5-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (47 mg, 38%).

Example 121-Benzyl-N-(2,2-dimethyl-propyl)-3-(2-methoxy-pyrimidin-5-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.22 mmol, 1.1 eq) was converted with 5-bromo-2-methoxypyrimidine (0.20mmol, 1.0 eq) to give desired1-benzyl-N-(2,2-dimethyl-propyl)-3-(2-methoxy-pyrimidin-5-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (91 mg, 96%).

Example 131-Benzyl-3-(5-chloro-thiophen-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.31 mmol, 1.1 eq) was converted with 2-bromo-5-chlorothiophene (0.28mmol, 1.0 eq) to give desired1-benzyl-3-(5-chloro-thiophen-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (24 mg, 18%).

Example 14[1-Benzyl-3-(2-methoxy-pyrimidin-5-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.31 mmol, 1.1 eq) was converted with 5-bromo-2-methoxypyrimidine(0.28, 1.0 eq) to give desired[1-benzyl-3-(2-methoxy-pyrimidin-5-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone(103 mg, 86%).

Example 15[1-Benzyl-4-methyl-3-pyrimidin-5-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.31 mmol, 1.1 eq) was converted with 5-bromopyrimidine (0.28 mmol, 1.0eq) to give desired[1-benzyl-4-methyl-3-pyrimidin-5-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone(46 mg, 39%).

Example 161-Benzyl-3-(3,5-dimethyl-isoxazol-4-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 4-bromo-3,5-dimethylisoxazole(0.30 mmol, 1.0 eq) to give desired1-benzyl-3-(3,5-dimethyl-isoxazol-4-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (44 mg, 32%).

Example 171-Benzyl-N-(2,2-dimethyl-propyl)-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with2-bromo-3-fluoro-5-(trifluoromethyl)pyridine (0.30 mmol, 1.1 eq) to givedesired1-benzyl-N-(2,2-dimethyl-propyl)-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (28 mg, 18%).

Example 181-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 2-bromo-5-chloropyrimidine (0.30mmol, 1.0 eq) to give desired1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (35 mg, 24%).

Example 191-Benzyl-3-(6-cyano-4-methylpyridin-3-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 5-bromo-4-methylpicolinonitrile(0.30 mmol, 1.0 eq) to give desired1-benzyl-3-(6-cyano-4-methylpyridin-3-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.061 mg, 42%).

Example 201-Benzyl-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 5-bromo-2-chloro-4-methylpyridine(0.30 mmol, 1.0 eq) to give desired1-benzyl-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (70 mg, 47%).

Example 211-Benzyl-N-(2,2-dimethyl-propyl)-3-(6-methoxy-4-methyl-pyridin-3-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with5-bromo-2-methoxy-4-methylpyridine (0.30 mmol, 1.0 eq) to give desired1-benzyl-N-(2,2-dimethyl-propyl)-3-(6-methoxy-4-methyl-pyridin-3-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (107 mg, 73%).

Example 221-Benzyl-3-(6-chloro-pyridazin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 3-bromo-6-chloropyridazine (0.30mmol, 1.0 eq) to give desired1-benzyl-3-(6-chloro-pyridazin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (36 mg, 25%).

Example 23[1-Benzyl-3-(3,5-dimethyl-isoxazol-4-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 4-bromo-3,5-dimethylisoxazole(0.30 mmol, 1.0 eq) to give desired[1-benzyl-3-(3,5-dimethyl-isoxazol-4-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone(43 mg, 32%).

Example 24[1-Benzyl-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with2-bromo-3-fluoro-5-(trifluoromethyl)pyridine (0.30 mmol, 1.0 eq) to givedesired[1-benzyl-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone(52 mg, 34%).

Example 25[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 2-bromo-5-chloropyrimidine (0.30mmol, 1.0 eq) to give desired[1-benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone(74 mg, 53%).

Example 265-[1-Benzyl-4-methyl-2-(morpholine-4-carbonyl)-5-(trifluoromethyl)-1H-pyrrol-3-yl]-4-methyl-pyridine-2-carbonitrile

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 5-bromo-4-methylpicolinonitrile(0.30 mmol, 1.0 eq) to give desired5-[1-benzyl-4-methyl-2-(morpholine-4-carbonyl)-5-(trifluoromethyl)-1H-pyrrol-3-yl]-4-methyl-pyridine-2-carbonitrile(47 mg, 33%).

Example 27[1-Benzyl-3-(6-chloro-4-methyl-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 5-bromo-2-chloro-4-methylpyridine(0.30 mmol, 1.0 eq) to give desired[1-benzyl-3-(6-chloro-4-methyl-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone(62 mg, 43%).

Example 28[1-Benzyl-3-(6-methoxy-4-methyl-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with5-bromo-2-methoxy-4-methylpyridine (0.30 mmol, 1.0 eq) to give desired[1-benzyl-3-(6-methoxy-4-methyl-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone(17 mg, 12%).

Example 29[1-Benzyl-3-(6-chloro-pyridazin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 3-bromo-6-chloropyridazine (0.30mmol, 1.0 eq) to give desired[1-benzyl-3-(6-chloro-pyridazin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone(32 mg, 23%).

Example 301-Benzyl-3-(5-methoxypyrimidin-2-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 2-bromo-5-methoxypyrimidine (0.30mmol, 1.0 eq) to give desired1-benzyl-3-(5-methoxypyrimidin-2-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(28 mg, 20%).

Example 311-Benzyl-3-(5-fluoropyridin-2-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 2-bromo-5-fluoropyridine (0.30mmol, 1.0 eq) to give desired1-benzyl-3-(5-fluoropyridin-2-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(25 mg, 18%).

Example 321-Benzyl-N,4-dimethyl-N-neopentyl-3-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 4-bromopyridazine (0.30 mmol, 1.0eq) to give desired1-benzyl-N,4-dimethyl-N-neopentyl-3-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(18 mg, 13%).

Example 331-Benzyl-3-(5-fluoropyrimidin-2-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 2-bromo-5-fluoropyrimidine (0.30mmol, 1.0 eq) to give desired1-benzyl-3-(5-fluoropyrimidin-2-yl)-N,4-dimethyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(7 mg, 5%).

Example 341-Benzyl-N,4-dimethyl-N-neopentyl-3-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 2-bromopyrazine (0.30 mmol, 1.0eq) to give desiredbenzyl-N,4-dimethyl-N-neopentyl-3-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(13 mg, 10%).

Example 351-Benzyl-N,4-dimethyl-N-neopentyl-3-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

According to general procedure A1-benzyl-N,4-dimethyl-N-neopentyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(0.33 mmol, 1.1 eq) was converted with 2-bromopyrimidine (0.30 mmol, 1.0eq) to give desired1-benzyl-N,4-dimethyl-N-neopentyl-3-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(14 mg, 10%).

Example 36(1-Benzyl-3-(5-fluoropyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 2-bromo-5-fluoropyridine (0.30mmol, 1.0 eq) to give desired(1-benzyl-3-(5-fluoropyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(42 mg, 31%).

Example 37(1-Benzyl-4-methyl-3-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 4-bromopyridazine (0.30 mmol, 1.0eq) to give desired(1-benzyl-4-methyl-3-(pyridazin-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(15 mg, 12%).

Example 38(1-Benzyl-3-(5-fluoropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 2-bromo-5-fluoropyrimidine (0.30mmol, 1.0 eq) to give desired(1-benzyl-3-(5-fluoropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(60 mg, 45%).

Example 39(1-Benzyl-4-methyl-3-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 2-bromopyrazine (0.30 mmol, 1.0eq) to give desired(1-benzyl-4-methyl-3-(pyrazin-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(55 mg, 43%).

Example 40(1-Benzyl-4-methyl-3-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone

According to general procedure A(1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(0.33 mmol, 1.1 eq) was converted with 2-bromopyrimidine (0.30 mmol, 1.0eq) to give desired(1-benzyl-4-methyl-3-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone(75 mg, 58%).

General Synthetic Route 2:

Example 411-Benzyl-3-(5-chloro-pyridin-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide 41a): Ethyl4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

This reaction was carried out in 4 batches of 1.2 g using the sameprocedure. To a mixture of ethyl 4-methyl-1H-pyrrole-2-carboxylate (1.2g, 7.8 mmol), K₂HPO₄ (4.05 g, 23.3 mmol) anddichlorotris(1,10-phenanthroline)-ruthenium(II) hydrate (112 mg, 0.15mmol) in Ar degassed dry MeCN (40 mL) was added CF₃SO₂Cl (1.24 mL, 11.6mmol). The reaction mixture was stirred for 5 d at RT adjacent to afluorescent light bulb (E27-23 W, 4000K, 165 mA.). All reaction mixtureswere combined and diluted with EtOAc and H₂O. The aqueous layer wasextracted with EtOAc (300 mL). The organic layers were combined and thesolvent was evaporated. The crude product was purified by flash CC(silica, gradient heptane/EtOAc, 9:1→4:1) to furnish the desired product(3.3 g, 48%). An impure batch was recrystallised from heptane (10 mL) togive another batch of pure title compound (1.55 g, 23%). Total yield:4.85 g (70%).

41b): Ethyl3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

To a solution of ethyl4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (1 g, 4.5 mmol) inMeCN (12 mL) was added K₂CO₃ (0.656 g, 4.8 mmol). The suspension cooledto 0° C. and NBS (0.85 g, 4.8 mmol) was portionwise added. The reactionmixture was stirred for a few minutes, warmed up to RT and H₂O (24 mL)was added. After 45 min, the solids which were formed were filtered offand washed with EtOH/H₂O (1:2, 30 mL) and dried on air, to afford thedesired product (1.18 g, 87%) as a white fluffy solid.

41c): Ethyl1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

To a solution of ethyl3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (600 mg,2.00 mmol) in dry MeCN (10 mL) was added K₂CO₃ (553 mg, 4.00 mmol) andbenzyl bromide (262 μL, 2.20 mmol). The suspension was stirred overnightat 80° C. Subsequently, silica (ca. 1 g) was added and the resultingsuspension was filtered off. The residue was washed with EtOAc (20 mL)and the combination of filtrate and washing was concentrated in vacuo.The residue was dissolved in heptane/DCM (1:1, few mL) and used forflash CC (silica, gradient heptane/EtOAc, 1:0→9:1) to result in 798 mg(97%, purity 95%) of the desired product as a clear oil.

41d): Ethyl1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

A round bottomed flask was charged with ethyl1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate(309 mg, 0.752 mmol) and transferred into a glove box. The pyrrole wasdissolved in dry and degassed dioxane (10 mL), addition of Pd₂(dba)₃ (33mg, 0.036 mmol) and XPhos (70 mg, 0.147 mmol) resulted in a purplesolution. Warming to around 90° C. resulted in a deep orange solution.Subsequently, dry and degassed Et₃N (331 μL, 2.38 mmol) and HBPin(4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 345 μL, 2.38 mmol) were added.The flask with the reaction mixture was transferred out of the glove boxand N₂ flushed condensor was placed on the flask. Heating at 100° C. for2 h resulted in a colourless solution with a voluminous whiteprecipitate and some palladium black. Carefully, saturated aqueous NH₄Cl(40 mL) was added (gas evolution) and the resulting mixture was stirredwell for 10 min. Addition of H₂O (10 mL) and EtOAc (40 mL) resulted inclear two phase system with palladium black. The organic layer wasdecanted, the residual aqueous layer was combined with a fresh portionof EtOAc (40 mL). The mixture was stirred well and the organic layer wasdecanted. The combination of organic layers was dried (Na₂SO₄) andconcentrated in vacuo. The residue was dissolved in DCM and used forflash CC (silica, gradient heptane/EtOAc, 1:0→4:1) to result in 279 mg(76%, purity 90%) of the desired product as a colourless oil.

41e): Ethyl1-benzyl-3-(5-chloropyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

A round bottomed flask was charged with ethyl1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate(232 mg, 0.478 mmol), 2-bromo-5-chloropyridine (153 mg, 0.796 mmol),PdCl₂(dppf) (43 mg, 0.053 mmol) and K₃PO₄ (338 mg, 1.59 mmol) andtransferred into a glove box. Addition of dry and degassed THF (15 mL)resulted in a slightly orange suspension. The flask with the reactionmixture was transferred out of the glove box and a nitrogen flushedcondensor was placed on the flask. Heating at 70° C. for 20 h wasfollowed by addition of 2-bromo-5-chloropyridine (77 mg, 0.398 mmol) andPdCl₂(dppf) (43 mg, 0.053 mmol). The reaction mixture was heated at 70°C. for 2 d, followed by concentration in vacuo. The residue was used forflash CC (silica, gradient heptane/EtOAc, 1:0→9:1) to result in 100 mg(37%, purity 75%) of impure product as a clear oil.

41 f):1-Benzyl-3-(5-chloropyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid

To a solution of impure ethyl1-benzyl-3-(5-chloropyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate(100 mg, 178 mmol) in DMSO (7 mL) were added crushed pellets of NaOH (28mg, 0.71 mmol). The reaction mixture was stirred at RT overnight.Subsequently, aqueous 1 M KHSO₄ (100 mL), H₂O (10 mL) and EtOAc (30 mL)were added to result in a clear two phase system. The layers wereseparated, the aqueous layer was extracted with EtOAc (30 mL). Thecombination of organic layers was washed with H₂O (20 mL) twice and withbrine, dried (Na₂SO₄) and concentrated in vacuo. The residue wasdissolved in DCM and used for preparative TLC (silica, heptane/EtOAc,2:1) to provide 78 mg (100%) of the desired product as a white solid.

41g): 1-Benzyl-3-(5-chloro-pyridin-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure B [described below]1-benzyl-3-(5-chloropyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid (40 mg, 0.091 mmol) was converted withN,2,2-trimethylpropan-1-amine hydrochloride [see section (B)](16.7 mg,0.122 mmol) to give desired1-benzyl-3-(5-chloro-pyridin-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (41 mg, 94%).

General Procedure B for Amide Coupling:

The corresponding carboxylic acid (1 eq) and the corresponding amine(1.0-1.5 eq) were dissolved in DME or DMF, DIPEA (3-5 eq) BOP-Cl(1.0-2.5 eq) were added. The reaction mixture was stirred at RT or, ifnecessary, 60° C. for 1-20 h and then cooled to RT. The reaction mixturewas poured in aqueous 1M KHSO₄ and the product was extracted using EtOAcor DCM (3×). The combined organic layers were washed with aqueous 1MKHSO₄ (2×), aqueous saturated NaHCO₃ (3×) and brine (2×) before dryingon Na₂SO₄ and concentration in vacuo. The product was purified usingflash CC (silica).

Example 42[1-Benzyl-3-(5-chloro-pyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone

According to general procedure C [see below]1-benzyl-3-(5-chloropyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid [see 41f)] (38 mg, 0.086 mmol) was converted with morpholine (17μL, 0.193 mmol) to give desired[1-benzyl-3-(5-chloro-pyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone(29 mg, 72%).

General Procedure C for Amide Coupling:

The corresponding carboxylic acid (1 eq) was suspended in dry DCM. Thecorresponding amine (0.8-2.5 eq) was added at RT or 0° C., followed byEDCl (1.0-1.5 eq) and HOAt (0.1-0.3 eq). The reaction mixture wasstirred at RT for 1-3 d. Subsequently it was either (A) brought onsilica or (B) diluted with H₂O and DCM, the aqueous layer extracted withDCM and the organics combined and concentrated in vacuo. The crudeproduct was purified by flash CC (silica), to afford the desiredproduct.

Example 431-Benzyl-3-(5-chloro-pyridin-2-yl)-N,4-dimethyl-N-(2-methylsulfonyl-ethyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure B [see 41g)]1-benzyl-3-(5-chloropyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid [see 41f)] (110 mg, 0.279 mmol) was converted with2-(methylamino)-1-(methylsulfonyl)ethane (46 mg, 0.334 mmol) to givedesired1-benzyl-3-(5-chloro-pyridin-2-yl)-N,4-dimethyl-N-(2-methylsulfonyl-ethyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (62 mg, 42%).

Example 44[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-(1,1-dioxo-[1,4]thiazinan-4-yl)-methanone44a): Ethyl1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

A flask was charged with ethyl1-benzyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate[see 41 d)] (947 mg, 2.1 mmol), Cs₂CO₃ (2.14 g, 6.50 mmol),5-chloro-2-iodopyrimidine (781 mg, 3.2 mmol), DME (16 mL) and H₂O (4mL). The suspension was purged with Ar for 50 min before PdCl₂(dppf)(158 mg, 0.2 mmol) was added. The reaction mixture was stirred at 95° C.for 2 h. The reaction mixture was cooled and filtered over celite andwashed with DCM (30 mL). The filtrate was concentrated in vacuo andpurified by flash CC (silica, gradient heptane/EtOAc, 1:0→9:1) to givethe desired product 412 mg (45%) as a colourless oil.

44b):1-Benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid

To a solution of ethyl1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate(613 mg, 1.45 mmol) in dry DMSO (10 mL) was added at 0° C. NaOH (191 mg,4.8 mmol). The reaction mixture was stirred at RT for 3 d. Aqueous 0.5 MKHSO₄ was added until pH 6 was reached and EtOAc (20 mL) was added. Thelayers were separated and the aquous layer was extracted with EtOAc (10mL). The combination of organic layers was washed 4× with brine (10 mL),dried (Na₂SO₄) and concentrated in vacuo. The residue was taken in Et₂O(20 mL) and the organic layer was washed 4× with brine (10 mL), dried(Na₂SO₄) and concentrated in vacuo to give 600 mg (‘105%’) of thedesired product as a yellow solid.

44c):[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-(1,4-dioxo-[1,4]thiazinan-4-yl)-methanone

According to general procedure C [see example 42]1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid (100 mg, 0.25 mmol) was converted with thiomorpholine 1,1-dioxide(42.7 mg, 0.32 mmol) to give desired[1-benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-(1,1-dioxo-[1,4]thiazinan-4-yl)-methanone(76 mg, 59%).

Example 45[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone

According to general procedure C [see example 42]1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid [see 44b)] (100 mg, 0.25 mmol) was converted with2,2-dimethylmorpholine (27.9 mg, 0.24 mmol) to give desired[1-benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone(79 mg, 63%).

Example 461-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-cyclopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure B [see 41g)]1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid [see 44b)] (100 mg, 0.25 mmol) was converted with cyclopropanamine(0.02 mL, 0.30 mmol) to give desired1-benzyl-3-(5-chloro-pyrimidin-2-yl)-N-cyclopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (58 mg, 53%).

Example 474-[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carbonyl]-piperazin-2-one

According to general procedure D [see below]1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid [see 44b)] (100 mg, 0.25 mmol) was converted with 2-oxopiperazine(32 mg, 0.32 mmol) to give desired4-[1-benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carbonyl]-piperazin-2-one(34 mg, 28%).

General Procedure D for Amide Coupling:

To a solution of the corresponding carboxylic acid (1 eq), Et₃N (2.5 eq)and the corresponding (1.0-1.5 eq) in DCM was added EDCl (1.2 eq) andHOAt (0.1-0.3 eq) at 0° C. under N₂. DMF was added and the reactionmixture was stirred overnight at RT. The reaction mixture was dilutedwith H₂O and DCM and stirred for 15 min. The organic layer was separatedand concentrated in vacuo. The product was purified using flash CC(silica). If necessary the product was purified further by reversedphase chromatography (C18) and the solvents were removed byfreeze-drying.

Example 481-Benzyl-N-(2-carbamoyl-2-methyl-propyl)-3-(5-chloro-pyrimidin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure B [see 41g)]1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid [see 44b)] (60 mg, 0.152 mmol) was converted with2,2-dimethyl-3-(methylamino)propanamide hydrochloride [see section (B)](30.3 mg, 0.182 mmol) to give desired1-benzyl-N-(2-carbamoyl-2-methyl-propyl)-3-(5-chloro-pyrimidin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (71 mg, 85%).

Example 491-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-(2-cyano-2-methyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure B [see 41g)]1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid [see 44b)] (60 mg, 0.152 mmol) was converted with2,2-dimethyl-3-(methylamino)propanenitrile hydrochloride [see section(B)] (27.0 mg, 0.182 mmol) to give desired1-benzyl-3-(5-chloro-pyrimidin-2-yl)-N-(2-cyano-2-methyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (41 mg, 51%).

Example 501-Benzyl-3-(5-chloro-pyridin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

The desired compound was synthesized following general synthetic route 2(see 41).

Example 511-Benzyl-N-isopropyl-N,4-dimethyl-3-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

The desired compound was synthesized following general synthetic route 1(see 01).

Example 521-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-isopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

The desired compound was synthesized following general synthetic route 1(see 01).

Example 531-Benzyl-3-(5-chloro-pyridin-2-yl)-N-isopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

The desired compound was synthesized following general synthetic route 1(see 01).

Example 571-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N,4-dimethyl-N-[2-methyl-2-(methylcarbamoyl)-propyl]-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure B [see 41g)]1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid [see 44b)] (120 mg, 0.303 mmol) was converted withN,2,2-trimethyl-3-(methylamino)propanamide hydrochloride [see section(B)] (82 mg, 0.455 mmol) to give desired1-benzyl-3-(5-chloro-pyrimidin-2-yl)-N,4-dimethyl-N-[2-methyl-2-(methylcarbamoyl)-propyl]-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (40 mg, 25%).

Example 581-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-[2-(dimethyl-carbamoyl)-2-methyl-propyl]-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure B [see 41g)]1-benzyl-3-(5-chloropyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid [see 44b)] (120 mg, 0.303 mmol) was converted withN,N,2,2-tetramethyl-3-(methylamino)propanamide hydrochloride [seesection (B)] (89 mg, 0.455 mmol) to give desired1-benzyl-3-(5-chloro-pyrimidin-2-yl)-N-[2-(dimethyl-carbamoyl)-2-methyl-propyl]-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (25 mg, 15%).

General Synthetic Route 3:

Example 551-Benzyl-3-(5-cyclopropyl-pyrazin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide 55a): Ethyl4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

A solution of ethyl 4-methyl-1H-pyrrole-2-carboxylate (9.42 g, 61.5mmol), CF₃SO₂Cl (13.04 mL, 123 mmol) and Fe₂SO₄.7H₂O (10.26 g, 36.9mmol) in DMF (275 mL) was cooled to 0° C. Subsequently, 30% aqueous H₂O₂(12.56 mL, 123 mmol) was added dropwise. Once effervescence had ceasedthe solution was stirred at RT for 1 h. The reaction mixture was pouredout in ice cold H₂O (1 L) while stirring. The solids were filtered offand the crude product was stored 5° C. for 6 d. The mixture wasdissolved in DMF (275 mL). Fe₂SO₄.7H₂O (10.26 g, 36.9 mmol) and CF₃SO₂Cl(13.04 mL, 123 mmol) were added and the reaction mixture was stirred for5 min, 30% aqueous H₂O₂ (12.56 mL, 123 mmol) was added dropwise to thesolution which was then stirred for 1 h at 0° C. The reaction mixturewas poured out in icecold H₂O (500 mL). The white precipitate wasfiltered off, washed with ice cold H₂O (2×25 mL). The residue wasdissolved in EtOAc (200 mL) and washed with brine (2×100 mL). Theorganics were dried over Na₂SO₄ and the solvent was removed underreduced pressure to give 6.33 g (41%) of the desired product.

55b): Ethyl3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

K₂CO₃ (3.96 g, 28.7 mmol) was added to a solution of ethyl4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (6.33 g, 25.2mmol) in MeCN (125 mL). The reaction mixture was cooled to 0° C. NBS(5.09 g, 28.6 mmol) was added portionwise and the reaction mixture wasstirred for 10 min. The reaction mixture was allowed to warm to RT. Ca.40 mL of MeCN was removed under reduced pressure. H₂O (170 mL) was addedand the mixture was stirred for 45 min. The precipitate was filteredoff, washed with H₂O (2×100 mL) and dried on a glass filter for 1 h. Thesolids were dissolved in Et₂O (200 mL), dried over Na₂SO₄ andconcentrated under reduced pressure to give 6.26 g (83%) of the desiredproduct.

55c): Ethyl1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate

A suspension of ethyl3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (6.26 g,20.86 mmol), K₂CO₃ (5.77 g, 41.7 mmol) and benzyl bromide (2.73 mL,22.95 mmol) in MeCN (100 mL) was stirred at 80° C. for 2 h. Benzylbromide (1.241 mL, 10.43 mmol) was added and the mixture was stirred for1 h at 80° C. The reaction mixture was allowed to cool to RT and thesolvents were removed under reduced pressure. The residue waspartitioned between EtOAc (200 mL) and H₂O (200 mL). The aqueous layerwas extracted with EtOAc (2×200 mL) and the combined organics were driedover Na₂SO₄ and concentrated under reduced pressure. The crude productwas coated onto silica and purified using flash cc (silica, gradient,heptane/CH₂Cl₂, 1:0→7:3) to give a pure and an impure batch. The impurebatch was coated onto silica and purified further using flash cc(silica, gradient heptane/CH₂Cl₂, 1:0→7:3) to give a pure and an impurebatch. The pure batches were combined to give 6.03 g (74%) of thedesired product.

55d):1-Benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid

NaOH (1.236 g, 30.9 mmol) was added to a cooled (0° C.) solution ofethyl1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate(6.03 g, 15.45 mmol) in DMSO (60 mL) while stirring. After 5 min, thereaction mixture was allowed to warm to RT. The flask was put in a waterbath at 40° C. for a few seconds which made the mixture betterstirrable. The reaction mixture was stirred for 18 h at RT. Aqueous 1MKHSO₄ (100 mL) was added and stirred for 5 min. The mixture waspartitioned between brine (100 mL) and EtOAc (100 mL). The aqueous layerwas diluted with H₂O (50 mL) and extracted with EtOAc (2×100 mL). Thecombined organics were washed with brine (3×100 mL) and dried overNa₂SO₄ to give 5.43 g (97%) of the desired product.

55e):1-Benzyl-3-bromo-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

BOP-Cl (2.81 g, 11.05 mmol) was added to a solution of1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid (2 g, 5.52 mmol) and DIPEA (2.89 mL, 16.57 mmol) in DME (40 mL).The suspension was stirred for 5 min. N-methylpropan-2-amine (1.140 mL,11.05 mmol) was added and the reaction mixture was stirred for 30 min.DIPEA (2.89 mL, 16.57 mmol) and BOP-Cl (2.81 g, 11.05 mmol) were addedand the reaction mixture was stirred for 5 min. N-methylpropan-2-amine(1.140 mL, 11.05 mmol) was added and the reaction mixture was stirredfor 30 min. BOP-Cl (1.406 g, 5.52 mmol) and DIPEA (0.965 mL, 5.52 mmol)were added and the reaction mixture was stirred for 5 min followed bythe addition of N-methylpropan-2-amine (0.570 mL, 5.52 mmol). Thereaction mixture was stirred for 30 min and quenched with a few drops ofH₂O. The solvent was removed under reduced pressure and the residue waspartitioned between half saturated aqueous NaHCO₃ (100 mL) and EtOAc(100 mL). The organic layer was washed with half saturated aqueousNaHCO₃ (100 mL) and brine (100 mL). The organic layer was separated anddried over Na₂SO₄. The solvent was removed under reduced pressure. Theproduct was coated on silica and purified using flash cc (silica,gradient heptane/i-Pr₂O, 1:0→3:1) to give 2.27 g (89%) of the desiredproduct.

55f):1-Benzyl-N-isopropyl-N,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

To a cooled (−78° C., acetone/dry ice) solution of1-benzyl-3-bromo-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(500 mg, 1.078 mmol) in dry THF (5 mL) under Ar, 1.6 M n-BuLi in hexanes(0.9 mL, 1.440 mmol) was added. The mixture was stirred for 10 min,4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.9 mL, 6.20 mmol) was addedand the reaction mixture was stirred for 1.5 h at −78° C. The reactionmixture was quenched with half saturated aqueous NH₄CI (4 mL) and storedat −20 C. for 18 h. The reaction mixture was partitioned between H₂O(100 mL) and EtOAc (100 mL). The organics were washed with brine (100mL) and dried over Na₂SO₄. The solvent was removed under reducedpressure and diluted with DMSO (2 mL). The product was purified usingreversed phase cc (C18, H₂O/MeCN/HCO₂H) to give 238 mg (47%) of thedesired product.

55g):1-Benzyl-3-(5-cyclopropyl-pyrazin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure E [described below]1-benzyl-N-isopropyl-N,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide(88 mg, 0.190 mmol) was converted with 2-bromo-5-cyclopropylpyrazine (57mg, 0.284 mmol) to give desired1-benzyl-3-(5-cyclopropyl-pyrazin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (97 mg, 83%).

General Procedure E for Suzuki Cross Coupling:

PdCl₂(dppf) (0.1 eq) was added to a 30 min Ar degassed solution of thecorresponding boronic ester (1 eq), the corresponding bromide (1.5 eq)and Cs₂CO₃ (3 eq) in DME:H₂O (4:1). The vial was placed in a pre-heatedoil bath at 100° C. and was stirred for 2-3 h under Ar. The reactionmixture was then filtered over silica. The filtrate was concentratedunder reduced pressure and diluted with DCM. The crude product waspurified using flash cc (silica).

Example 561-Benzyl-3-(5-cyclopropyl-pyrimidin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide

According to general procedure E [see 55g)]1-benzyl-N-isopropyl-N,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide[see 55f)] (119 mg, 0.256 mmol) was converted with2-chloro-5-cyclopropylpyrimidine (59 mg, 0.384 mmol) to give desired1-benzyl-3-(5-cyclopropyl-pyrimidin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide (86 mg, 74%).

Example 591-Benzyl-N-isopropyl-N,4-dimethyl-3-(1-methyl-1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide

The desired compound was synthesized following general synthetic route 1(see 01).

Example 60

According to general procedure E [see 55g)]1-benzyl-N-isopropyl-N,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide[see 55f)] (315 mg, 0.678 mmol) was converted with2-bromo-5-chloro-3-(methylsulfinyl)pyridine [see section B] (259 mg,1.018 mmol) to give desired SC-60 (270 mg, 78%).

Example 61

According to general procedure E [see 55g)]1-benzyl-N-isopropyl-N,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide[see 55f)] (80 mg, 0.172 mmol) was converted with2-bromo-5-(methylsulfinyl)pyridine (57 mg, 0.258 mmol) to give desiredSC-61 (68 mg, 66%).

Section (B)

N,2,2-Trimethylpropan-1-amine hydrochloride

a): tert-Butyl neopentylcarbamate

To a solution of 2,2-dimethylpropan-1-amine (17.90 g, 205 mmol) in DCM(150 mL) was dropwise added a solution of Boc₂O (44.8 g, 205 mmol) inDCM (50 mL) at 0° C. After complete addition, stirring was continued atRT overnight. The solvent was removed under reduced pressure and theresidue co-evaporated with DCM (3×). EtOAc (250 mL) was added and themixture was washed with H₂O (2×250 mL). The organic layer was dried(Na₂SO₄) and evaporated under reduced pressure, to give 36.98 g (96%) ofthe desired product.

b): tert-Butyl methyl(neopentyl)carbamate

A solution of tert-butyl neopentylcarbamate (37.0 g, 198 mmol) in dryDMF (100 mL) was added to a suspension of 60% NaH in mineral oil (15.8g, 395 mmol) in dry DMF (200 mL) under N₂ in 10 min and the reactionmixture was stirred for 1 h. To the reaction mixture was added Mel (30.9mL, 494 mmol) in 10 min while cooling with an icebath and the reactionmixture was stirred at RT overnight. The reaction mixture was quenchedwith ice/H₂O (600 mL) and extracted with Et₂O (1 L). The organic layerwas washed with brine, dried (Na₂SO₄) and concentrated to result in thedesired product (45.6 g, ‘115%’).

c): N,2,2-Trimethylpropan-1-amine hydrochloride

To a solution of tert-butyl methyl(neopentyl)carbamate (45.6 g, max. 198mmol) in dry 1,4-dioxane (200 mL) was dropwise added 4M HCl in dioxane(200 mL, 800 mmol) and the reaction mixture was stirred overnight. Thereaction mixture was concentrated and stirred in Et₂O for 1 d. Theproduct was filtered under N₂ stream, washed with a small amount of Et₂O(2×) and dried on filter for 10 min yielding the desired product (26.0g, 95% over two steps).

2,2-Dimethyl-3-(methylamino)propanamide hydrochloride

a): Ethyl 3-((tert-butoxycarbonyl)amino)-2,2-dimethylpropanoate

At 0° C., ethyl 3-amino-2,2-dimethylpropanoate hydrochloride (4.5 g,24.77 mmol) was dissolved in a mixture of DCM (150 mL) and pentane (150mL). Et₃N (4.14 mL, 29.7 mmol) was added, followed by Boc₂O (5.41 g,24.77 mmol) and the white suspension was stirred at RT for 20 h. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between H₂O (100 mL) and i-Pr₂O (100 mL). The aqueous layerwas extracted with i-Pr₂O (100 mL) and the combined organic layers werewashed with H₂O (2×50 mL) and brine (2×50 mL) before drying on Na₂SO₄and concentration in vacuo to give the desired product (6.05 g, 100%) asa yellow oil.

b): Ethyl 3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoate

To a cooled (0° C.) solution of ethyl3-((tert-butoxycarbonyl)amino)-2,2-dimethylpropanoate (6.05 g, 24.66mmol) in dry DMF (40 mL) was added 60% NaH in mineral oil (1.085 g, 27.1mmol). The mixture was stirred for 5 min at 0° C., then warmed up to RTover 15 min. The mixture was cooled to 0° C. again and Mel (3.1 mL, 49.6mmol) was added via a syringe over 2 min. The mixture was stirred at RTfor 3 h. The reaction mixture was poured out in aqueous 1M KHSO₄ (100mL) with vigorous stirring and the product was extracted withi-Pr₂O/EtOAc (1:1, v/v, 250 mL). The organic layer was washed withaqueous 1M KHSO₄ (2×50 mL), saturated aqueous NaHCO₃ (2×50 mL) andaqueous 1M Na₂S₂O₃ (2×50 mL) before washing with brine (2×50 mL) anddrying on Na₂SO₄. The solvent was removed in vacuo to give the desiredproduct (5.72 g, 89%) as a colorless oil.

c): 3-((tert-Butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoic acid

A suspension of LiOH.H₂O (9 g, 216 mmol) in H₂O (25 mL) was added to asolution of ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoate (5.6 g,21.59 mmol) in a mixture of THF (25 mL) and EtOH (25 mL). The mixturewas stirred at 60° C. for 3 h. The volatiles were removed in vacuo andthe aqueous mixture was cooled in an ice bath. Aqueous 1M KHSO₄ (250 mL)was added. The product was extracted with EtOAc (3×75 mL) and thecombined organic layers were washed with aqueous 1M KHSO₄ (2×50 mL) andbrine (2×50 mL) before drying on Na₂SO₄ and concentration in vacuo togive the desired product (4.9 g, 98%) as a yellow oil which crystallisedon standing.

d): tert-Butyl (3-amino-2,2-dimethyl-3-oxopropyl)(methyl)carbamate

To a solution of3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoic acid (4.22g, 18.25 mmol) in EtOAc (200 mL) was added CDl (3.55 g, 21.89 mmol). Themixture was stirred at RT for 1.5 h. The reaction mixture was cooled inan ice bath and aqueous 25% NH₄OH (34 mL, 219 mmol) was added and theresulting suspension was stirred at RT for 2 h. The reaction mixture wasconcentrated in vacuo to approximately 200 mL. The residue was washedwith saturated aqueous NaHCO₃ (3×50 mL), aqueous 1M KHSO₄ (2×50 mL) andbrine (2×50 mL) before drying on Na₂SO₄ and concentration in vacuo togive a white solid. The product was crystallised from hot EtOH and driedon air to give the desired product (2.8 g, 66%) as colorless crystals.

e): 2,2-Dimethyl-3-(methylamino)propanamide hydrochloride

To a solution of tert-butyl(3-amino-2,2-dimethyl-3-oxopropyl)(methyl)carbamate (1.8 g, 7.82 mmol)in DCM (40 mL) was added 4 M HCl in dioxane (39 mL, 156 mmol). Themixture was stirred at RT for 3 h. The reaction mixture was concentratedin vacuo to give the desired product (1.27 g, 98%) as a white solid.

2,2-Dimethyl-3-(methylamino)propanenitrile hydrochloride

a): tert-Butyl (2-cyano-2-methylpropyl)(methyl)carbamate

A solution of tert-butyl(3-amino-2,2-dimethyl-3-oxopropyl)(methyl)carbamate [see step d)synthesis of 2,2-dimethyl-3-(methylamino)propanamide hydrochloride] (1g, 4.34 mmol) in pyridine (10 mL) was cooled in an ice bath. POCl₃ (405μL, 4.34 mmol) was added via a syringe and the resulting whitesuspension was stirred at 0° C. for 30 min. The reaction mixture waspoured out in aqueous 5M HCl (26 mL) and the product was extracted withEtOAc (1×50 mL, 1×25 mL). The combined organic layers were washed withaqueous 1M HCl (2×20 mL), saturated aqueous NaHCO₃ (2×20 mL) and brine(2×20 mL) before drying on Na₂SO₄ and concentration in vacuo to give thedesired product (689 mg, 74%) as a colorless oil.

b): 2,2-Dimethyl-3-(methylamino)propanenitrile hydrochloride

To a solution of tert-butyl (2-cyano-2-methylpropyl)(methyl)carbamate(0.689 g, 3.25 mmol) in DCM (16 mL) was added 4M HCl in dioxane (16.2mL, 64.9 mmol) and the solution was stirred at RT for 1 h. The reactionmixture was concentrated in vacuo to give a white solid. The product wascrystallised from hot EtOH to give the desired product (287 mg, 59%) ascolorless crystals.

N,2,2-Trimethyl-3-(methylamino)propanamide hydrochloride

a): Ethyl 3-((tert-butoxycarbonyl)amino)-2,2-dimethylpropanoate

To a cooled solution of3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoic acid [seeabove] (4.98 g, 27.4 mmol) and Et₃N (4.59 mL, 32.9 mmol) in DCM (200 mL)was added Boc₂O (5.98 g, 27.4 mmol) under N₂. The mixture was stirred atRT for 1 h. The reaction mixture was concentrated in vacuo and theresidue was suspended in i-Pr₂O (100 mL) and filtered off. The residuewas washed with i-Pr₂O (2×25 mL) and the filtrate was washed withbrine/H₂O (1:1, 2×20 mL) and brine (2×20 mL) before drying on Na₂SO₄ andconcentration in vacuo to give the desired product (6.23 g, 93%).

b): Ethyl 3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoateand Methyl 3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoate

To a cooled solution of ethyl3-((tert-butoxycarbonyl)amino)-2,2-dimethylpropanoate (6.23 g, 25.4mmol) in dry DMF (40 mL) was added NaH; 60 wt % in mineral oil (7 g, 175mmol). The white suspension was warmed to RT over 45 min. The mixturewas cooled to 0° C. and Mel (3.16 mL, 50.8 mmol) was added. The mixturewas stirred at 0° C. for 30 min. The mixture was warmed to RT andstirred for 2 h. The mixture was very carefully poured out in a cooledsolution of aqueous 1 M KHSO₄ (150 mL) in ice water (150 mL) under afast stream of N₂. The product was extracted with i-Pr₂O (200 mL) andEtOAc (200 mL) and the combined organic layers were washed with aqueous1 M KHSO₄ (2×50 mL), aqueous saturated NaHCO₃ (2×50 mL) and brine (2×50mL) before drying on Na₂SO₄ and concentration in vacuo. At 0° C., theproduct was dissolved in dry DMF (40 mL) and NaH; 60 wt % in mineral oil(0.508 g, 12.70 mmol) was added. The mixture was stirred for 30 min. Mel(0.79 mL, 12.70 mmol) was added and the stirring was continued at RT for3 h. The mixture was poured out in aqueous 1 M KHSO₄ (15 mL) and theproduct was extracted with i-Pr₂O/EtOAc (1:1, 2×100 mL). The combinedorganic layers were washed with aqueous 1 M KHSO₄ (2×20 mL), aqueoussaturated NaHCO₃ (2×20 mL) and brine (2×20 mL) before drying on Na₂SO₄and concentration in vacuo. The product was purified using flash cc(silica, heptane/EtOAc 1:0→6:4) to give a mixture of the desiredproducts (5.2 g, 80%).

c): 3-((tert-Butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoic acid

To a solution of ethyl3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoate (5.21 g,12.46 mmol, 62%) and methyl3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoate (5.21 g,8.07 mmol, 38%) in THF/EtOH (1:1, 50 mL) was added LiOH.H₂O (8.39 g, 200mmol) and H₂O (25 mL). The solution was heated to 60° C. for 1.5 h. Theheating was continued at 70° C. for 1 h. The volatiles were removed invacuo. The residue was cooled in an ice bath and acidified using aqueous1 M KHSO₄ (200 mL). The product was extracted with EtOAc (2×100 mL) andthe combined organic layers were washed with aqueous 1 M KHSO₄ (2×20 mL)and brine (2×20 mL) before drying on Na₂SO₄ and concentration in vacuoto give the desired product (4.57 g, 96%).

d): tert-Butyl(2,2-dimethyl-3-(methylamino)-3-oxopropyl)(methyl)carbamate

To a solution of3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoic acid (1.0g, 4.32 mmol) and BOP-Cl (1.321 g, 5.19 mmol) in dry DME (10 mL) wasadded DIPEA (0.995 mL, 5.62 mmol) and the resulting white suspension wasstirred at RT for 5 min. MeNH₂.HCl (0.438 g, 6.49 mmol) was added,followed by DliPEA (1.531 mL, 8.65 mmol) and the suspension was stirredRT for 30 min. More MeNH₂—HCl (0.584 g, 8.65 mmol) and DiPEA (1.53 mL,8.65 mmol) were added and the stirring was continued at RT for 20 h.More DIPEA (1.15 mL, 6.49 mmol) and MeNH₂.HCl (438 mg, 6.49 mmol) wereadded and the stirring was continued at RT for 1 h. The reaction mixturewas poured out in aqueous 1 M KHSO₄ (50 mL) and the product wasextracted with EtOAc (2×50 mL). The combined organic layers were washedwith aqueous 1 M KHSO₄ (2×20 mL), aqueous saturated NaHCO₃ (2×20 mL) andbrine (2×20 mL) before drying on Na₂SO₄ and concentration in vacuo togive the desired product (823 mg, 78%).

e): N,2,2-Trimethyl-3-(methylamino)propanamide hydrochloride

At RT, 4 M HCl in dioxane (16.84 mL, 67.4 mmol) was slowly added to asolution of tert-butyl(2,2-dimethyl-3-(methylamino)-3-oxopropyl)(methyl)carbamate (0.823 g,3.37 mmol) in DCM (17 mL). The mixture was stirred at RT for 3 h. Thereaction mixture was concentrated in vacuo to give the desired product(642 mg, ‘105%’).

N,2,2-Trimethyl-3-(methylamino)propanamide hydrochloride

a): tert-Butyl(3-(dimethylamino)-2,2-dimethyl-3-oxopropyl)(methyl)carbamate

To a solution of3-((tert-butoxycarbonyl)(methyl)amino)-2,2-dimethylpropanoic acid [seeabove] (1.0 g, 4.32 mmol) in dry DME (15 mL) was added BOP-Cl (1.321 g,5.19 mmol), followed by dimethylamine; 2 M in THF (7.8 mL, 15.60 mmol)and the reaction mixture was stirred at RT for 3 h. More dimethylamine;2 M in THF (1 mL, 2 mmol) was added and the stirring was continued for20 h. The reaction mixture was poured out in aqueous 1 M KHSO₄ (20 mL)and the product was extracted with i-Pr₂O (2×50 mL). The combinedorganic layers were washed with aqueous 1 M KHSO₄ (2×25 mL), aqueous 1 MNaOH (2×25 mL) and brine (2×25 mL) before drying on Na₂SO₄ andconcentration in vacuo to give the desired product (764 mg, 68%).

b): N,2,2-Trimethyl-3-(methylamino)propanamide hydrochloride

To a solution of tert-butyl(3-(dimethylamino)-2,2-dimethyl-3-oxopropyl)(methyl)carbamate (0.764 g,2.96 mmol) in DCM (17 mL) was added 4 M HCl in dioxane (14.79 mL, 59.1mmol) and the reaction mixture was stirred at RT for 1 h. The reactionmixture was concentrated in vacuo to give the desired product (670 mg,‘116%’).

2-Bromo-5-chloro-3-(methylsulfinyl)pyridine

b): 2-Bromo-5-chloro-3-(methylsulfinyl)pyridine

Aqueous 30% H₂O₂ (0.257 mL, 2.52 mmol) was added to a solution of2-bromo-5-chloro-3-(methylthio)pyridine (500 mg, 2.096 mmol) in1,1,1,3,3,3-hexafluoro-2-propanol (5 mL). The reaction mixture wasstirred for 18 h at RT. The reaction was quenched with aqueous 1 MNa₂S₂O₃ (3 mL, 3 mmol) and the solvent was removed under reducedpressure. The residue was co-evaporated with EtOH (30 mL). The productwas taken up in EtOAc (30 mL), filtered over cotton wool and thefiltrate was evaporated. The product was coated on silica and purifiedusing flash cc (silica, gradient heptane/EtOAc, 1:0→1:1) to afford 481mg (90%) of the desired product.

Analytical Data:

Material and Methods for LC/MS Analytics: Hardware: Coupled Agilent 1290Infinity UHPLC-TOF System; LC-Module: MTP-Handler: Agilent, ModelBenchCel 2R; Themostatic Control Autoinjector: Agilent, Modell G4226A;Column oven: Agilent, Model G1316C; DAD: Agilent, Model G4212A; BinaryPump: Agilent, Model G4220A; Time Of Fliqht Mass Spectrometer: Agilent6224; Ion source: Dual ESI; Column: Supplier: Waters; Type: Acquity UPLCHSS T3 1.8 μm (Part No. 186003538); Dimensions: 2.1×50 mm; Eluents:Eluent A: Water from Millipore Ultrapure water System: Milli-Q Integral3+0.1% Formic acid; Eluent B: MeCN, Merck KGaA: LiChrosolv Hypergradefor LC-MS (1.00029.9010)+0.1% Formic acid; Formic acid: Merck KGaA:Suprapure 98-100% (1.11670.1000); LC-Method: Flow: 2.5 mL/min; Runtime:1.2 min; Gradient: Start 2% B, 1 min 100% B, 1.09 min 100% B, 1.11 min2% B, 1.2 min 2% B Stop; Columntemperature: 80° C.; UV: 190-400 nm;MS-Method: Ion Polarity: Positive; Gas Temperature: 325° C.; Gas Flow:10 mL/min

Ex. Mass UV254- No. R¹, R², R³ m, n R⁴ R⁵ Het N(R⁹)(R¹⁰) Mass Foundpurity 01 H, H, H 0, 1 CF₃ CH₃

474.52 Yes 100 02 H, H, H 0, 1 CF₃ CH₃

473.53 Yes 100 03 H, H, H 0, 1 CF₃ CH₃

459.50 Yes 100 04 H, H, H 0, 1 CF₃ CH₃

446.51 Yes  94 05 H, H, H 0, 1 CF₃ CH₃

460.45 Yes 100 06 H, H, H 0, 1 CF₃ CH₃

459.46 Yes  98 07 H, H, H 0, 1 CF₃ CH₃

445.43 Yes 100 08 H, H, H 0, 1 CF₃ CH₃

432.44 Yes  99 09 H, H, H 0, 1 CF₃ CH₃

432.48 Yes  95 10 H, H, H 0, 1 CF₃ CH₃

418.41 Yes  96 11 H, H, H 0, 1 CF₃ CH₃

444.49 Yes  94 12 H, H, H 0, 1 CF₃ CH₃

474.52 Yes  96 13 H, H, H 0, 1 CF₃ CH₃

482.99 Yes 100 14 H, H, H 0, 1 CF₃ CH₃

460.45 Yes 100 15 H, H, H 0, 1 CF₃ CH₃

430.42 Yes 100 16 H, H, H 0, 1 CF₃ CH₃

461.52 Yes  98 17 H, H, H 0, 1 CF₃ CH₃

529.49 Yes 100 18 H, H, H 0, 1 CF₃ CH₃

478.94 Yes 100 19 H, H, H 0, 1 CF₃ CH₃

482.54 Yes 100 20 H, H, H 0, 1 CF₃ CH₃

491.98 Yes 100 21 H, H, H 0, 1 CF₃ CH₃

487.56 Yes 100 22 H, H, H 0, 1 CF₃ CH₃

478.94 Yes 100 23 H, H, H 0, 1 CF₃ CH₃

447.45 Yes 100 24 H, H, H 0, 1 CF₃ CH₃

515.42 Yes 100 25 H, H, H 0, 1 CF₃ CH₃

464.87 Yes  99 26 H, H, H 0, 1 CF₃ CH₃

468.47 Yes 100 27 H, H, H 0, 1 CF₃ CH₃

477.91 Yes 100 28 H, H, H 0, 1 CF₃ CH₃

473.49 Yes 100 29 H, H, H 0, 1 CF₃ CH₃

464.87 Yes  97 30 H, H, H 0, 1 CF₃ CH₃

474.52 Yes  98 31 H, H, H 0, 1 CF₃ CH₃

461.50 Yes  98 32 H, H, H 0, 1 CF₃ CH₃

444.49 Yes  97 33 H, H, H 0, 1 CF₃ CH₃

462.48 Yes  98 34 H, H, H 0, 1 CF₃ CH₃

444.49 Yes  97 35 H, H, H 0, 1 CF₃ CH₃

444.49 Yes  98 36 H, H, H 0, 1 CF₃ CH₃

447.43 Yes  98 37 H, H, H 0, 1 CF₃ CH₃

430.42 Yes  97 38 H, H, H 0, 1 CF₃ CH₃

448.41 Yes  98 39 H, H, H 0, 1 CF₃ CH₃

430.42 Yes  97 40 H, H, H 0, 1 CF₃ CH₃

430.42 Yes  98 41 H, H, H 0, 1 CF₃ CH₃

477.95 Yes 100 42 H, H, H 0, 1 CF₃ CH₃

463.88 Yes  96 43 H, H, H 0, 1 CF₃ CH₃

513.96 Yes  99 44 H, H, H 0, 1 CF₃ CH₃

512.93 Yes 100 45 H, H, H 0, 1 CF₃ CH₃

492.92 Yes 100 46 H, H, H 0, 1 CF₃ CH₃

434.84 Yes 100 47 H, H, H 0, 1 CF₃ CH₃

477.87 Yes  98 48 H, H, H 0, 1 CF₃ CH₃

507.94 Yes  98 49 H, H, H 0, 1 CF₃ CH₃

489.92 Yes 100 50 H, H, H 0, 1 CF₃ CH₃

449.90 Yes 100 51 H, H, H 0, 1 CF₃ CH₃

418.46 Yes  97 52 H, H, H 0, 1 CF₃ CH₃

436.86 Yes  98 53 H, H, H 0, 1 CF₃ CH₃

435.87 Yes 100 54 H, H, H 0, 1 CF₃ CH₃

450.88 Yes  93 55 H, H, H 0, 1 CF₃ CH₃

456.50 Yes 100 56 H, H, H 0, 1 CF₃ CH₃

456.50 Yes 100 57 H, H, H 0, 1 CF₃ CH₃

521.96 Yes 100 58 H, H, H 0, 1 CF₃ CH₃

535.99 Yes 100 59 H, H, H 0, 1 CF₃ CH₃

418.20 Yes >98 60 H, H, H 0, 1 CF₃ CH₃

477.17 Yes >98 61 H, H, H 0, 1 CF₃ CH₃

511.13 Yes

2. Assay Descriptions and Biological Data: 2.1 Fluorescent Assay forCaV2.2 Channels Using Potassium Depolarization to Induce Channel Opening

Human CaV2.2 channels were stably expressed in HEK293 cells togetherwith alpha2-delta and beta subunits of voltage gated calcium channels.In addition, an inwardly rectifying potassium channel (Kir2.3) wasstably expressed in these cells to augment control of the cell membranepotential by the concentration of extracellular potassium ions. Raise ofthe extracellular potassium concentration leads to depolarization of themembrane potential and thus regulates the voltage dependent state ofCaV2.2 channels. For preparation, cells were seeded in blackpoly-D-lysine coated 96-well plates (Becton Dickinson, Biocoat 4640) in100 μL medium [500 mL DMEM/F-12 plus Glutamax (Invitrogen 31331-093)plus 5.5 mL MEM NEAA 100× (Invitrogen 11140-035) plus 50 mL FBSdecomplemented (Invitrogen 10270-106) plus 200 μg/mL Geneticin(Invitrogen 10131-027) plus 50 μg/mL Hygromycin B (Invitrogen 10687-010)plus 2 μg/mL Blasticidin (anti-bl5b Invivo-Gen) plus 0.2 μg/mL Puromycin(A 11138-03)] at a cell density of 30.000 cells per well. Plates wereincubated at 37° C. (5% CO₂) for 20 to 23 h. On the day of experimentmedium was discarded and cells were loaded with Fluo 4 by addition of100 μL of basic assay buffer (10 mM HEPES, 1 mM KCl, 149 mM NaCl, 0.8 mMCaC₂, 1.7 mM MgCl₂, 10 mM Glucose, 0.1% BSA. pH 7.4) containing 2 μMFluo 4 (Molecular Probes; F-14201), 0.01% pluronic acid (MolecularProbes; P-6866) and 2.5 mM probenecid (Molecular Probes; P36400). Cellswere incubated in the dark at 25° C. for 60 min. Then dye containingbuffer was discarded and 100 μL basic (1 mM KCl) or alternative (30 mMKCl) assay buffer was added. The alternative assay buffer containedaltered concentrations of KCl (30 mM) and NaCl (120 mM) and was used inorder to promote the inactivated channel state. After that 25 μL ofbasic or alternative assay buffer with or without test compound wereadded and cells were incubated again in the dark at 25° C. for 15 min.Fluorescence intensity was measured on a FLIPR 3 instrument (MolecularDevices Corp., Sunnyvale, Calif.) with excitation at 480 nm and emissionat 535 nm. After continuously reading fluorescence for 30 sec, 50 μL ofbasic assay buffer containing 210 mM KCl (NaCl omitted) were added fordepolarization. Peak fluorescent signal intensity was determined and theamplitude of the peak signal, normalized to base line, was used tomeasure channel inhibition by test compounds.

The following table summarizes the inhibitory activity of exemplifiedcompounds according to the present invention.

Example No. Activity * 01 B 02 C 03 C 04 A 05 C 06 B 08 C 09 B 10 C 11 B12 B 13 B 14 C 15 C 16 B 17 B 18 A 19 B 20 B 21 B 22 A 23 B 24 A 25 A 26B 27 B 28 B 29 C 30 B 31 A 32 B 33 A 34 B 35 B 36 B 37 C 38 C 39 C 40 C41 A 42 A 43 A 44 B 45 A 46 C 47 C 48 A 49 A 50 A 51 B 52 C 53 B 54 A 56A 58 A 61 B * %-Inhib (CaV2.2) @3 μM @30 mM KCl: “A”: %-Inhibition >95%;“B”: %-Inhibition >75% up to ≦95%; “C”: %-Inhibition >40% up to ≦75%,“D”: %-Inhibition >30% up to ≦40%.

2.2 Electrophysiological Assessment of Calcium Channel Activity

Patch-clamp recordings were performed using HEK293 cells stablyexpressing human Cav2.2. Cells were plated in T150 flasks and grown ahumidified incubator at 37° C. and under 5% CO₂ to approximately 50-60%confluency. Cells were maintained at 30° C. for 48 hrs prior torecording. On the day of the experiment, cells were harvested withTrypLE cell detachment solution (Invitrogen) diluted to 25% withphosphate buffered saline and maintained in 50% cell culture media, 50%NaCl based external saline (in mM, 140 NaCl, 4 KCl, 1 MgCl₂, 2 CaCl₂, 5Glucose, 10 HEPES, pH 7.4) up to several hours prior to experiment.

Currents were recorded at room temperature (21-23° C.) using thePatchliner planar array technology (Nanion). Patchliner is a multi-wellwhole-cell automated patch clamp device that operates asynchronouslywith fully integrated fluidics. Capacitance and series resistancecompensation was automated and no correction for liquid junctionpotential was employed. Leak was subtracted on-line. Whole-cellpatch-clamp recordings were obtained using extracellular salineconsisting of (mM): 145 TEA-CI, 10 BaCl₂, 10 HEPES, 10 Glucose. The pHwas adjusted to 7.35 with NaOH and the osmolarity was adjusted to 310mOsm with sucrose. Intracellular solution consisted of (mM): 50 CsCl, 60CsF, 10 NaCl, 20 EGTA, 5 BAPTA, 10 HEPES. Prior to an experiment, 5 mMMgATP and 0.3 NaGTP were added, the pH was adjusted to 7.2 with CsOH andthe osmolarity was adjusted to 290 mOsm with sucrose.

A voltage pulse protocol was utilised to assess compound inhibition.Cells were held at a holding potential of −60 mV and channels wereactivated using a 10 ms test pulse to +30 mV activated every 10 seconds(0.1 Hz). Increasing concentrations of compound were applied toindividual cells with 5 minutes at each test concentration. Compoundswere prepared in DMSO as 10 mM stock solutions and subsequent 1:3 serialdilutions performed. Final dilution of 1:1000 in external solutionresulted in a final DMSO concentration of 0.1%. For each cell, currentresponses were normalised to dimethyl sulfoxide vehicle control togenerate concentration-response curves. When multiple doses wereachieved per cell, IC50 values were calculated from the fits of the Hillequation to the data. The form of the Hill equation used was: Relativecurrent=(100/(1+(IC50/conc)̂Slope)). A selection of the foregoingexemplified compounds was tested under these conditions: Severalcompounds are potent inhibitors (IC50<5 μM) or even very potentinhibitors (IC50<2 μM).

1. A compound of general formula (I),

wherein n represents 0, 1 or 2; m represents 0 or 1 with the provisothat n≧m; X is selected from the group consisting of O, S, NH andN—C₁₋₆-alkyl; R¹, R² and R³, are each independently of one anotherselected from the group consisting of H; F; Cl; Br; I; NO₂; CN;C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂; C(═O)—H; C(═O)—C₁₋₆-alkyl;C(═O)—OH; C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH); C(═O)—NH₂;C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂; C(═N—OH)—H;C(═N—OH)—C₁₋₆-alkyl; C(═N—O—C₁₋₆-alkyl)-H;C(═N—O—C₁₋₆-alkyl)-C₁₋₆-alkyl; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; O—C(═O)—O—C₁₋₆-alkyl;O—(C═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(C₁₋₆-alkyl)₂; O—S(═O)₂—C₁₋₆-alkyl;O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₆-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)(C₁₋₆-alkyl); O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)(C₁₋₆-alkyl);N(H)—C(═O)—N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—NH₂;N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂OH;N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl); N(H)—S(═O)₂N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—OH; N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—NH₂;N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl);S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocyclyl;O—C₃₋₁₀-cycloalkyl and O-(3 to 7 membered heterocyclyl); R⁴ representsCH₂F; CHF₂, or CF₃; R⁵ represents H, C₁₋₆-alkyl, branched or unbranched,unsubstituted or mono- or poly-substituted, a C₃₋₁₀-cycloalkyl or a 3 to7 membered heterocyclyl, in each case unsubstituted or mono- orpolysubstituted; OH; O—C₁₋₆-alkyl; NH₂; N(H)—C₁₋₆-alkyl; N(—C₁₋₆-alkyl)₂or SO₂(—C₁₋₆-alkyl); Het represents 5-, 6-, 8-, 9- or 10-memberedheteroaryl, each substituted by zero or one or two or three substituentsof the group consisting of R⁶, R⁷ and R⁸, wherein R⁶, R⁷ and R⁸, areeach independently of one another selected from the group consisting ofF; Cl; Br; I; NO₂; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; CF₂Cl; CFCl₂;C(═O)—H; C(═O)—C₁₋₆-alkyl; C(═O)—OH; C(═O)—O—C₁₋₆-alkyl; C(═O)—N(H)(OH);C(═O)—NH₂; C(═O)—N(H)(C₁₋₆-alkyl); C(═O)—N(C₁₋₆-alkyl)₂; C(═N—OH)—H;C(═N—OH)—C₁₋₆-alkyl; C(═N—O—C₁₋₆-alkyl)-H;C(═N—O—C₁₋₆-alkyl)-C₁₋₆-alkyl; OH; OCF₃; OCF₂H; OCFH₂; OCF₂Cl; OCFCl₂;O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; O—C(═O)—O—C₁₋₆-alkyl;O—(C═O)—N(H)(C₁₋₆-alkyl); O—C(═O)—N(C₁₋₆-alkyl)₂; O—S(═O)₂—C₁₋₆-alkyl;O—S(═O)₂—OH; O—S(═O)₂—O—C₁₋₆-alkyl; O—S(═O)₂—NH₂;O—S(═O)₂—N(H)(C₁₋₆-alkyl); O—S(═O)₂—N(C₁₋₆-alkyl)₂; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; N(H)—C(═O)—C₁₋₆-alkyl;N(H)—C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—NH₂; N(H)—C(═O)—N(H)(C₁₋₆-alkyl);N(H)—C(═O)—N(C₁₋₆-alkyl)₂; N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-C(═O)—NH₂;N(C₁₋₆-alkyl)-C(═O)—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; N(H)—S(═O)₂OH;N(H)—S(═O)₂—C₁₋₆-alkyl; N(H)—S(═O)₂—O—C₁₋₆-alkyl; N(H)—S(═O)₂—NH₂;N(H)—S(═O)₂—N(H)(C₁₋₆-alkyl); N(H)—S(═O)₂N(C₁₋₆-alkyl)₂;N(C₁₋₆-alkyl)-S(═O)₂—OH; N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; N(C₁₋₆-alkyl)-S(═O)₂—NH₂;N(C₁₋₆-alkyl)-S(═O)₂—N(H)(C₁₋₆-alkyl);N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; SH; SCF₃; SCF₂H; SCFH₂; SCF₂Cl;SCFCl₂; S—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl); orS(═O)₂—N(C₁₋₆- alkyl)₂; C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocyclyl;O—C₃₋₁₀-cycloalkyl or O-(3 to 7 membered heterocyclyl); R⁹ represents H,C₁₋₁₀-alkyl, branched or unbranched, unsubstituted or mono- orpoly-substituted; C₃₋₁₀-cycloalkyl or 3 to 10 membered heterocyclyl,wherein said C₃₋₁₀-cycloalkyl or 3 to 10 membered heterocyclyl in eachcase may be unsubstituted or mono- or poly-substituted and wherein saidC₃₋₁₀-cycloalkyl or 3 to 10 membered heterocyclyl may be in each caseconnected via a C₁₋₈-alkylene group, which in turn may be branched orunbranched and may be unsubstituted or mono- or polysubstituted; R¹⁰represents H, C₁₋₁₀-alkyl; C₃₋₁₀-cycloalkyl, 3 to 10 memberedheterocyclyl or heteroaryl, wherein said C₃₋₁₀-cycloalkyl, 3 to 10membered heterocyclyl or heteroaryl in each case may be unsubstituted ormono- or poly-substituted and wherein said C₃₋₁₀-cycloalkyl, 3 to 10membered heterocyclyl or heteroaryl may be in each case connected via aC₁₋₈-alkylene group, which in turn may be branched or unbranched and maybe unsubstituted or mono- or polysubstituted; or R⁹ and R¹⁰ togetherwith the nitrogen atom connecting them form a 3 to 10 memberedheterocyclyl; wherein in each case said C₁₋₆-alkyl and C₁₋₁₀-alkyl maybe branched or unbranched; unsubstituted or mono- or polysubstituted;and wherein in each case said C₃₋₁₀-cycloalkyl, 3 to 7 memberedheterocyclyl, 3 to 10 membered heterocyclyl or heteroaryl may beunsubstituted or mono- or poly-substituted; optionally in the form of asingle stereoisomer or a mixture of stereoisomers, in form of the freecompound and/or a physiologically acceptable salt and/or aphysiologically acceptable solvate thereof.
 2. A compound according toclaim 1, wherein n represents 1 and m represents 0; and R¹, R² and R³,are each independently of one another selected from the group consistingof H; F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH; OCF₃; OCF₂H; OCFH₂;O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; NH₂; N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂;SCF₃; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH;S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; S(═O)₂—N(H)(C₁₋₆-alkyl); orS(═O)₂—N(C₁₋₆-alkyl)₂, wherein in each case C₁₋₆-alkyl may be branchedor unbranched.
 3. A compound according to claim 1, wherein R⁴ representsCHF₂ or CF₃.
 4. A compound according to claim 1, wherein R⁵ is selectedfrom the group consisting of H, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, methoxy, ethoxy,methylsulfonyl, 2-oxetyl, 3-oxetyl, 2-tetrahydrofuranyl and3-tetrahydrofuranyl.
 5. A compound according to claim 1, wherein thecompound of general formula (I) is a compound according to generalformula (Ia) or (Ib),

wherein Het, R⁹ and R¹⁰ are defined according to claim
 1. 6. A compoundaccording to claim 1, wherein Het is selected from pyrrol, furanyl,thienyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl,thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl,benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzotriazolyl, pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl,quinazolinyl, cinnolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl,1,7-naphthyridinyl, 1,8-naphthyridinyl, 2,3-naphthyridinyl,2,6-naphthyridinyl and 2,7-naphthyridinyl.
 7. A compound according toclaim 1, wherein R⁶, R⁷ and R⁸ are each independently of one anotherselected from the group consisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H;CFH₂; OH; OCF₃; OCF₂H; OCFH₂; O—C₁₋₆-alkyl; O—C(═O)—C₁₋₆-alkyl; NH₂;N(H)(C₁₋₆-alkyl); N(C₁₋₆-alkyl)₂; SCF₃; S(═O)—C₁₋₆-alkyl;S(═O)₂—C₁₋₆-alkyl; S(═O)₂—OH; S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂;S(═O)₂—N(H)(C₁₋₆-alkyl); S(═O)₂—N(C₁₋₆-alkyl)₂; C₃₋₆-cycloalkyl andO—C₃₋₆-cycloalkyl; wherein in each case said C₁₋₆-alkyl may be branchedor unbranched and wherein in each case said C₃₋₆-cycloalkyl may beunsubstituted or mono- or polysubstituted.
 8. A compound according toclaim 1, wherein R⁹ represents H or C₁₋₆-alkyl, branched or unbranched,unsubstituted or substituted with 1, 2, 3, 4 or 5 substituentsindependently from one another selected from the group consisting of OH,═O, O—C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl;N(H)—C(═O)—C₁₋₆-alkyl, and N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; and R¹⁰represents H; or C₁₋₆-alkyl, branched or unbranched, unsubstituted orsubstituted with 1, 2, 3, 4 or 5 substituents independently from oneanother selected from the group consisting of F, Cl, CF₃, CN, OH, ═O,OCF₃, O—C₁₋₆-alkyl, O—(C═O)C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl,S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl,S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, N(H)—C(═O)—NH₂,N(H)—C(═O)—N(H)(C₁₋₆-alkyl), N(H)—C(═O)—N(C₁₋₆-alkyl)₂,N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂, O—C(═O)—N(H)(C₁₋₆-alkyl),O—C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—NH₂, C(═O)—N(H)(C₁₋₆-alkyl),C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—C₁₋₆-alkyl, andN(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; or C₃₋₆-cycloalkyl, unsubstituted orsubstituted with 1, 2, 3, 4 or 5 substituents independently from oneanother selected from the group consisting of F, Cl, CN, CF₃, ═O, OCF₃,C₁₋₆-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, O—(C═O)C₁₋₆-alkyl,S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl,S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl,N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂, O—C(═O)—N(H)(C₁₋₆-alkyl),O—C(═O)—N(C₁₋₆-alkyl)₂, N(H)—C(═O)—NH₂, N(H)—C(═O)—N(H)(C₁₋₆-alkyl),N(H)—C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—NH₂, C(═O)—N(H)(C₁₋₆-alkyl),C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—C₁₋₆-alkyl, andN(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; wherein said C₃₋₆-cycloalkyl isoptionally connected via C₁₋₆-alkylene, branched or unbranched, which inturn may be unsubstituted or substituted with 1, 2, 3, 4 or 5substituents independently from one another selected from the groupconsisting of F, Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl andC₁₋₆-alkylen-OH; or 3-7-membered heterocyclyl, which is unsubstituted orsubstituted with 1, 2, 3, 4 or 5 substituents independently from oneanother selected from the group consisting of F, Cl, CN, CF₃, ═O, OCF₃,C₁₋₆-alkylen-OH, C₁₋₆ alkyl, OH, O—C₁₋₆-alkyl, O—(C═O)C₁₋₆-alkyl,S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl,S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl,N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂, O—C(═O)—N(H)(C₁₋₆-alkyl),O—C(═O)—N(C₁₋₆-alkyl)₂, N(H)—C(═O)—NH₂, N(H)—C(═O)—N(H)(C₁₋₆-alkyl),N(H)—C(═O)—N(C₁₋₆-alkyl)₂, (C═O)C₁₋₆-alkyl, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl;N(H)—C(═O)—C₁₋₆-alkyl, and N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl, wherein said3-7-membered heterocyclyl is optionally connected via C₁₋₆-alkylene,branched or unbranched, which in turn may be unsubstituted orsubstituted with 1, 2, 3, 4 or 5 substituents independently from oneanother selected from the group consisting of F, Cl, CF₃, ═O, OCF₃, OH,O—C₁₋₆-alkyl and C₁₋₆-alkylen-OH; or heteroaryl, which is unsubstitutedor substituted with 1, 2, 3, 4 or 5 substituents independently from oneanother selected from the group consisting of F, Cl, CN, CF₃, OCF₃,C₁₋₆-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, O—(C═O)C₁₋₆-alkyl,S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl,S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl,N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂, O—C(═O)—N(H)(C₁₋₆-alkyl),O—C(═O)—N(C₁₋₆-alkyl)₂, N(H)—C(═O)—NH₂, N(H)—C(═O)—N(H)(C₁₋₆-alkyl),N(H)—C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—NH₂, C(═O)—N(H)(C₁₋₆-alkyl),C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; N(H)—C(═O)—C₁₋₆-alkyl, andN(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl, wherein said heteroaryl is optionallyconnected via C₁₋₆-alkylene, branched or unbranched, which in turn maybe unsubstituted or substituted with 1, 2, 3, 4 or 5 substituentsindependently from one another selected from the group consisting of F,Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl and C₁₋₆-alkylen-OH.
 9. A compoundaccording to claim 1, wherein R⁹ and R¹⁰ together with the nitrogen atomconnecting them form a 3 to 7-membered heterocyclyl, unsubstituted orsubstituted with 1, 2, 3, 4 or 5 substituents selected from the groupconsisting of F, Cl, CN, CF₃, ═O, OH, C₁₋₆-alkyl, O—C₁₋₆-alkyl,C₁₋₆-alkylen-OH, OCF₃, SO₂(C₁₋₆-alkyl), SO₂NH₂, SO₂N(H)C₁₋₆-alkyl,SO₂N(C₁₋₆-alkyl)₂, C₁₋₆-alkylen-SO₂(C₁₋₆-alkyl), NH₂, NH(C₁₋₆-alkyl),N(C₁₋₆-alkyl)₂, (C═O)C₁₋₆-alkyl, C₃₋₆-cycloalkyl or 3 to 7 memberedheterocyclyl, in each case unsubstituted or mono- or polysubstituted.10. A compound according to claim 1, wherein R⁹ represents H orC₁₋₆-alkyl; and R¹⁰ represents C₃₋₆-cycloalkyl, which is unsubstitutedor substituted with 1, 2, 3, 4 or 5 substituents independently from oneanother selected from the group consisting of F, Cl, CF₃, ═O, OCF₃, OH,O—C₁₋₆-alkyl, C₁₋₆-alkylen-OH and C₁₋₆-alkyl; or 3-7-memberedheterocyclyl, which contains 1 or 2 heteroatoms or heteroatom groupsindependently from one another selected from the group consisting of O,S, S(═O), S(═O)₂, NH and N—C₁₋₆-alkyl, and which is unsubstituted orsubstituted with 1, 2, 3, 4 or 5 substituents independently from oneanother selected from the group consisting of F, Cl, CF₃, OCF₃, CN,C₁₋₆-alkyl, C₁₋₆-alkylen-OH and O—C₁₋₆-alkyl; or heteroaryl, whichcontains at least one nitrogen atom and which is unsubstituted orsubstituted with 1, 2 or 3 substituents independently from one anotherselected from the group consisting of F, Cl, CN, CF₃, OCF₃,C₁₋₆-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,S(═O)₂—NH₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, O—C(═O)—NH₂, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; or apart structure of general formula SF-III

wherein x represents 0, 1 or 2; y represents 0, 1 or 2; z represents 0,1 or 2; on the condition that the sum of x, y and z is 1, 2, 3, 4, 5 or6; R¹¹ and R¹² are independently from one another selected from H orC₁₋₆-alkyl; or R¹¹ and R¹² together with the carbon atom connecting themform a C₃₋₆-cycloalkyl or a 3-7-membered heterocyclyl, which contains 1or 2 heteroatoms or heteroatom groups independently from one anotherselected from the group consisting of O, S, S(═O), S(═O)₂, NH andN—C₁₋₆-alkyl, wherein said C₃₋₆-cycloalkyl or 3-7-membered heterocyclylmay be unsubstituted or substituted with 1, 2, 3, 4 or 5 substituentsindependently from one another selected from the group consisting of F,Cl, CF₃, OCF₃, CN, C₁₋₆-alkyl and O—C₁₋₆-alkyl; R¹³ is selected from thegroup consisting of H, F, Cl, CN, CF₃, OCF₃, C₁₋₈-alkylen-OH, OH,O—C₁₋₆-alkyl, O—(C═O)C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl, S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂,NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, N(H)—C(═O)—C₁₋₆-alkyl,N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl, N(H)—S(═O)—C₁₋₆-alkyl,N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl, N(H)—S(═O)₂—C₁₋₆-alkyl,N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, C(═O)—NH₂, C(═O)—N(H)(C₁₋₆-alkyl),C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl, N(H)—C(═O)—NH₂,N(H)—C(═O)—N(H)(C₁₋₆-alkyl), N(H)—C(═O)—N(C₁₋₆-alkyl)₂,N(H)—C(═O)—O—C₁₋₆-alkyl; O—C(═O)—NH₂, O—C(═O)—N(H)(C₁₋₆-alkyl),O—C(═O)—N(C₁₋₆-alkyl)₂; or represents C₃₋₆-cycloalkyl, which isunsubstituted or substituted with 1, 2, 3, 4, or 5 substituentsindependently from one another selected from the group consisting of F,Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₆-alkylen-OH and C₁₋₆-alkyl; or3-7-membered heterocyclyl, which contains 1 or 2 heteroatoms orheteroatom groups independently from one another selected from the groupconsisting of O, S, S(═O), S(═O)₂, NH and N—C₁₋₆-alkyl, and which isunsubstituted or substituted with 1, 2, 3, 4 or 5 substituentsindependently from one another selected from the group consisting of F,Cl, CF₃, OCF₃, CN, C₁₋₆-alkyl and O—C₁₋₆-alkyl; or heteroaryl, whichcontains at least one nitrogen atom and which is unsubstituted orsubstituted with 1, 2 or 3 substituents independently from one anotherselected from the group consisting of F, Cl, CN, CF₃, OCF₃,C₁₋₆-alkylen-OH, C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, S(═O)₂—C₁₋₆-alkyl,S(═O)₂—NH₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂, O—C(═O)—NH₂, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl; or R⁹and R¹⁰ together with the nitrogen atom connecting them form aheterocyclyl, selected from the group consisting of

wherein R¹⁴ denotes 0, 1, 2, 3 or 4 substituents which are in each caseindependently of each other selected from the group consisting of F, Cl,CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₆-alkylen-OH,C₁₋₆-alkylen-SO₂(C₁₋₆-alkyl), SO₂(C₁₋₆-alkyl) and C₁₋₆-alkyl; or R¹⁴denotes at least two substituents, wherein two substituents R¹⁴ standtogether for a C₁₋₆-alkylen-group, substituted or unsubstituted, whereinoptionally one or more C-atoms of the C₁₋₆-alkylen-group is replaced bya heteroatom or heteroatom group, selected of O, N—R¹⁵, S, S(O) andS(O)₂, and wherein these two substituents R¹⁴ are positioned atdifferent carbon atoms of the heterocyclyl, so the C₁₋₆-alkylen-grouprepresents a bridge to form a bicyclic heterocyclyl; or R¹⁴ denotes atleast two substituents, wherein two substituents R¹⁴ stand together fora C₂₋₆-alkylen-group, substituted or unsubstituted, wherein optionallyone or more C-atoms of the C₂₋₆-alkylen-group is replaced by aheteroatom or heteroatom group, selected of O, N—R¹⁵, S, S(O) and S(O)₂,and wherein these two substituents R¹⁴ are positioned at the same carbonatom of the heterocyclyl, so the C₂₋₆-alkylen-group forms aspiro-heterocyclyl; and R¹⁵ represents H, C₁₋₆-alkyl or (C═O)C₁₋₆-alkyl.11. A compound according to claim 1, wherein the compound of generalformula (I) is a compound according to general formula (Ia) or (Ib),

wherein Het is select from group consisting of pyrrol, thienyl,pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridinyl,pyrazinyl, pyrimidinyl and pyridazinyl, each substituted by zero or oneor two substituents of the group consisting of R⁶ and R⁷, wherein R⁶ andR⁷ are each independently of one another selected from the groupconsisting of F; Cl; CN; C₁₋₆-alkyl; CF₃; CF₂H; CFH₂; OH; OCF₃; OCF₂H;OCFH₂; O—C₁₋₆-alkyl; S(═O)—C₁₋₆-alkyl; S(═O)₂—C₁₋₆-alkyl; cyclopropyl orO-cyclopropyl; R⁹ represents H or C₁₋₆-alkyl; and R¹⁰ representsC₃₋₆-cycloalkyl, which is unsubstituted or substituted with 1, 2 or 3substituents independently from one another selected from the groupconsisting of F, Cl, CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₆-alkylen-OHand C₁₋₆-alkyl; or represents a part structure of general formula SF-III

wherein x represents 0, 1 or 2; y represents 0, 1 or 2; z represents 0,1 or 2; on the condition that the sum of x, y and z is 1, 2, 3, 4, 5 or6; R¹¹ and R¹² are independently from one another selected from H orC₁₋₆-alkyl; R¹³ is selected from the group consisting of H, F, Cl, CN,OH, O—C₁₋₆-alkyl, O—(C═O)C₁₋₆-alkyl, S(═O)—C₁₋₆-alkyl,S(═O)₂—C₁₋₆-alkyl, S(═O)₂—NH₂, S(═O)₂—N(H)C₁₋₆-alkyl,S(═O)₂—N(C₁₋₆-alkyl)₂, NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂,N(H)—C(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl,N(H)—S(═O)—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)—C₁₋₆-alkyl,N(H)—S(═O)₂—C₁₋₆-alkyl, N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl, C(═O)—NH₂,C(═O)—N(H)(C₁₋₆-alkyl), C(═O)—N(C₁₋₆-alkyl)₂, C(═O)—O—C₁₋₆-alkyl,N(H)—C(═O)—NH₂, N(H)—C(═O)—N(H)(C₁₋₆-alkyl), N(H)—C(═O)—N(C₁₋₆-alkyl)₂;or R⁹ and R¹⁰ together with the nitrogen atom connecting them form aheterocyclyl, selected from the group consisting of

wherein R¹⁴ denotes 0, 1 or 2 substituents which are in each caseindependently of each other selected from the group consisting of F, Cl,CF₃, ═O, OCF₃, OH, O—C₁₋₆-alkyl, C₁₋₆-alkylen-OH,C₁₋₆-alkylen-SO₂(C₁₋₆-alkyl), SO₂(C₁₋₆-alkyl) and C₁₋₆-alkyl; and R¹⁵represents H, C₁₋₆-alkyl or (C═O)C₁₋₆-alkyl.
 12. The compound accordingto claim 1, which is selected from the group consisting of 011-Benzyl-N-(2,2-dimethyl-propyl)-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 02[1-Benzyl-3-[3-fluoro-5-(trifluoromethyl)-pyridin-2-yl]-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;031-Benzyl-3-(3,5-dimethyl-isoxazol-4-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 04[1-Benzyl-3-(3,5-dimethyl-isoxazol-4-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;051-Benzyl-3-(6-cyano-4-methyl-pyridin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 065-[1-Benzyl-4-methyl-2-(morpholine-4-carbonyl)-5-(trifluoromethyl)-1H-pyrrol-3-yl]-4-methyl-pyridine-2-carbonitrile;071-Benzyl-3-(6-chloro-4-methyl-pyridin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 08[1-Benzyl-3-(6-chloro-4-methyl-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;091-Benzyl-N-(2,2-dimethyl-propyl)-3-(6-methoxy-4-methyl-pyridin-3-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 10[1-Benzyl-3-(6-methoxy-4-methyl-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;111-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyrazin-2-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 12[1-Benzyl-4-methyl-3-pyrazin-2-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;131-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyridazin-4-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 14[1-Benzyl-4-methyl-3-pyridazin-4-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;151-Benzyl-N-(2,2-dimethyl-propyl)-3-(5-fluoro-pyridin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 16[1-Benzyl-3-(5-fluoro-pyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;171-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 18[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;191-Benzyl-N-(2,2-dimethyl-propyl)-3-(5-fluoro-pyrimidin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 20[1-Benzyl-3-(5-fluoro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;211-Benzyl-N-(2,2-dimethyl-propyl)-3-(5-methoxy-pyrimidin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 221-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyrimidin-2-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 23[1-Benzyl-4-methyl-3-pyrimidin-2-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;241-Benzyl-3-(6-chloro-pyridazin-3-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 25[1-Benzyl-3-(6-chloro-pyridazin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;26[1-Benzyl-4-methyl-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;27[1-Benzyl-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;281-Benzyl-3-(5-chloro-pyridin-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 291-Benzyl-3-(5-chloro-pyridin-2-yl)-N,4-dimethyl-N-(2-methylsulfonyl-ethyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 30[1-Benzyl-3-(5-chloro-pyridin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;311-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-(2-cyano-2-methyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 321-Benzyl-N-(2-carbamoyl-2-methyl-propyl)-3-(5-chloro-pyrimidin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 334-[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carbonyl]-piperazin-2-one;34[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-(2,2-dimethyl-morpholin-4-yl)-methanone;35[1-Benzyl-3-(5-chloro-pyrimidin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-(1,1-dioxo-[1,4]thiazinan-4-yl)-methanone;361-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-cyclopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 371-Benzyl-N-(2,2-dimethyl-propyl)-3-(2-methoxy-pyrimidin-5-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 38[1-Benzyl-3-(2-methoxy-pyrimidin-5-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;391-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-pyrimidin-5-yl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 40[1-Benzyl-4-methyl-3-pyrimidin-5-yl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;411-Benzyl-3-(5-chloro-thiophen-2-yl)-N-(2,2-dimethyl-propyl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 421-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 431-Benzyl-N-(2,2-dimethyl-propyl)-3-(6-hydroxy-pyridin-3-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 44[1-Benzyl-3-(6-hydroxy-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;451-Benzyl-N-(2,2-dimethyl-propyl)-3-(6-methoxy-pyridin-3-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 46[1-Benzyl-3-(6-methoxy-pyridin-3-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;471-Benzyl-N-(2,2-dimethyl-propyl)-3-(5-methoxy-pyrazin-2-yl)-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 48[1-Benzyl-3-(5-methoxy-pyrazin-2-yl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl]-morpholin-4-yl-methanone;491-Benzyl-N-(2,2-dimethyl-propyl)-N,4-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 501-Benzyl-3-(5-chloro-pyridin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 511-Benzyl-N-isopropyl-N,4-dimethyl-3-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 521-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-isopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 531-Benzyl-3-(5-chloro-pyridin-2-yl)-N-isopropyl-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 541-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 551-Benzyl-3-(5-cyclopropyl-pyrazin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 561-Benzyl-3-(5-cyclopropyl-pyrimidin-2-yl)-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 571-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N,4-dimethyl-N-[2-methyl-2-(methylcarbamoyl)-propyl]-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 581-Benzyl-3-(5-chloro-pyrimidin-2-yl)-N-[2-(dimethyl-carbamoyl)-2-methyl-propyl]-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; 591-Benzyl-N-isopropyl-N,4-dimethyl-3-(1-methyl-1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide;601-Benzyl-N-isopropyl-N,4-dimethyl-3-[5-(methylsulfinyl)-pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; and 611-Benzyl-3-[5-chloro-3-(methylsulfinyl)-pyridin-2-yl]-N-isopropyl-N,4-dimethyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylicacid amide; optionally in the form of a single stereoisomer or a mixtureof stereoisomers, in the form of the free compound and/or aphysiologically acceptable salt or solvate thereof.
 13. A pharmaceuticalcomposition comprising at least one compound according to claim
 1. 14. Amethod for the treatment and/or prophylaxis of one or more disordersselected from the group consisting of pain; stroke; mood disorders;epilepsy; schizophrenia, and neurodegenerative disorders, said methodcomprising administering to a patient in need thereof an effectiveamount therefor of at least one compound according to claim
 1. 15. Themethod according to claim 14, which is carried out for the treatmentand/or prophylaxis of pain, wherein the pain is one or more of acutepain and/or chronic pain and/or visceral pain and/or headache painand/or inflammatory pain and/or mixed pain.